Cellular calcium signaling in the aging brain

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Journal of Chemical Neuroanatomy journal homepage: www.elsevier.com/locate/jchemneu

Review

Cellular calcium signaling in the aging brain Remya Chandranb,1, Mantosh Kumara,1,2, Lakshmi Kesavana,1,2, Reena Sarah Jacoba,1,3, Sowmya Gunasekarana,1,3, Sethu Lakshmia,1,2, C. Sadasivanb, Omkumar R.V.a,⁎ a b

Molecular Neurobiology Division, Rajiv Gandhi Centre for Biotechnology, Thycaud, P. O., Thiruvananthapuram, Kerala, 695 014, India Department of Biotechnology and Microbiology, Kannur University, Thalassery Campus, Palayad, Kannur, Kerala, 670 661, India

A R T I C L E I N F O

A B S T R A C T

Keywords: Aging Calcium signaling Neuronal calcium homeostasis Calcium channels Aging associated neurodegenerative disease Oxidative stress Excitotoxicity

Aging in the biological system is an irreversible process. In the initial stages of lifespan aging improves survival skills of an organism while in the later stages aging reduce the survival skills. Aging is associated with changes in several cellular and molecular functions among which calcium signaling is a prominent one. Calcium signaling is essential for many vital functions of the brain and even minor impairments in calcium signaling can lead to deleterious consequences including neuronal death. Calcium signaling proteins are pursued as promising drug targets for many aging related diseases. This review attempts to summarize changes in calcium signaling in the brain as a result of aging.

1. Introduction Aging is an uncontrollable, multifaceted and complex process in the form of accumulation of multiple cellular damages and pathologies over time due to failure in cellular signaling, repair and compensatory mechanisms (Kirkwood and Kirkwood, 2003). Aging is also associated with increased free radical production and oxidative stress, which in turn causes global cellular damage and death (Harman, 1965; Migliore and Coppedè, 2009). López-Otín et al. (2013) proposed nine candidate hallmarks viz. genomic instability, epigenetic alterations, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, loss of proteostasis, altered intra-cellular communication and telomere attrition as the major contributors to aging. Differences in lifestyle and the effect of environmental and genetic factors account for the variations in aging process among individuals. A gradual decline in cellular functions caused by abnormal activation or inhibition of signaling pathways during aging can lead to various human pathologies such as cancer, diabetes, cardiovascular disorders and neurodegenerative diseases (Niccoli and Partridge, 2012) thereby increasing the disease burden. Upon aging, brain undergoes both morphological and functional modifications that might alter motor and sensory systems, sleep, memory and learning (Timiras, 2007). Inefficient calcium (Ca2+) homeostasis and alterations in neurotransmission are considered as major factors leading to aging. Since

neuronal Ca2+ homeostasis and signaling are indispensable for regulating functions such as synaptic transmission (Berridge, 1998), synaptic plasticity and cell survival (Lamont and Weber, 2012; Malenka and Nicoll, 1999), any disturbance in Ca2+ homeostasis can lead to a variety of pathologies (Kirischuk and Verkhratsky, 1996). The accumulation of oxidative and metabolic stress together with a decline in the normal antioxidant defense mechanisms with age, impairs Ca2+ homeostasis in neurons, making them more vulnerable to neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington's disease (HD) and Amyotrophic lateral sclerosis (ALS) (Mattson et al., 2000a; Wojda et al., 2008). Advances in health care and living standards and consequent increase in the average life expectancy have led to a significant increase in the aged population. This in turn has increased the burden of aging associated problems. According to the latest estimates and projections from World Population Aging (United Nations report, 2015), the number of people aged 60 years or above has increased markedly. By 2050, the global population of older people is projected to be reaching almost 2.1 billion and the number of people aged 80 years or above, ‘the oldest-old' population, is predicted to triple by 2050. Reports also suggest a dramatic increase in the older population in developing countries, for e.g. in India, the numbers might reach approximately 323 million by 2050 (Help Age India, 2015). The increased life expectancy and prevalence of neurodegenerative

⁎

Corresponding author. E-mail address: [email protected] (R.V. Omkumar). 1 Equal Contribution. 2 Research Scholar, University of Kerala. 3 Research Scholar, Manipal Academy of Higher Education, Manipal – 576 104, India. https://doi.org/10.1016/j.jchemneu.2017.11.008 Received 26 May 2017; Received in revised form 3 September 2017; Accepted 7 November 2017 0891-0618/ © 2017 Elsevier B.V. All rights reserved.

Please cite this article as: Chandran, R., Journal of Chemical Neuroanatomy (2017), https://doi.org/10.1016/j.jchemneu.2017.11.008

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

most prominent changes of the aging immune system is thymic involution, which contributes to reduced T cell variability in elderly people and increased susceptibility to infections and diseases (Palmer, 2013). (6) The role of inflammatory processes in age related diseases have been stated in the inflamm-aging theory (Franceschi et al., 2000). Aging disrupts the balance between pro- and anti-inflammatory components, promoting chronic inflammation. Inflammatory factors in the aging brain are known to originate from activation of microglia and astrocytes (Grabert et al., 2016; Salminen et al., 2011). (7) The neuroendocrine theory proposes that aging is due to changes in neural and endocrine function. The impaired balance between these two systems results in the loss of homeostasis and thereby increases the risk of death (Fabris, 1991). Consistent with this theory, the hypothalamus pituitary adrenal axis, the main regulatory system, loses efficiency with age (Weinert and Timiras, 2003). (8) The cross linking theory/glycation hypothesis of aging, proposed by John Bjorksten (Bjorksten, 1968), states that aging is caused by a progressive accumulation of cross linked macromolecules through a process called glycosylation or glycation, which damage cells and tissues, impairing cellular functions, leading to aging. Amyloid fibrils found in the brains of AD patients is a glycation product of amyloid beta (Aβ) peptides (Vitek et al., 1994), which initiates several death signals in AD.

diseases necessitates better understanding of the aging processes and mechanisms associated with it. AD is the most common type of dementia and it is the sixth leading cause of death in the United States (Heron et al., 2009). New cases of AD in the U.S are expected to increase by 110% by 2050 and the number of people aged 65 and older with AD is projected to be 13.8 million (Alzheimer's Association, 2016). Developing countries too have a similar scenario with approximately 4.1 million people in India being affected by dementia according to the World Alzheimer Report (Prince, 2015). This review focuses on the cellular and molecular mechanisms underlying the cause and effect of dysregulation in Ca2+ homeostasis during brain aging and age-related neurodegenerative diseases like AD, PD, HD and ALS. Age-related changes in Ca2+ channels are also discussed which can further help in developing potent therapeutic agents that can possibly reverse these changes to prevent or delay the progression of the diseases with aging. 2. Theories on aging Several theories have been proposed to explain the normal aging process. According to Hayflick (Hayflick, 2007), “The common denominator that underlies all modern theories of biological aging is change in molecular structure and, hence, function”. The proposed theories of aging have been reviewed by Tosato et al. (Tosato et al., 2007) and are listed below: (1) The evolutionary theory about aging says that aging occurs as a result of decline in the force of natural selection (Haldane, 1941). For example, a balance between somatic cell maintenance and reproduction is determined by activation of stress responses such as unfolded protein responses (UPR) in the endoplasmic reticulum (ER). UPRER activation is positively correlated to longevity and negatively correlated to fertility. Once an organism’s reproductive goals are attained, there is less evolutionary pressure to maintain the stress responses and therefore the power of natural selection declines, resulting UPRER loss and that further contributes to the aging process (Taylor, 2016). (2) Free radical, mitochondrial and somatic mutation theory of aging, in which free radical and mitochondrial theory of aging suggests that accumulation of ROS in cells could be responsible for cellular damage and aging (Harman, 1956), where mitochondria play an important role in the initiation of free radical production. The mutations in mitochondrial DNA (mtDNA) increases with age and are mainly responsible for the deficiency in cellular energetics, leading to enhanced ROS production and oxidative damage (Harman, 1972). Somatic mutation theory of aging postulates that oxidative damage may be a reason for somatic mutations and accumulation of these mutations over the years enhances cellular senescence (Morley, 1995). There are many studies that are in favor and in contradiction to the free radical theory of aging (Arking et al., 2000; Doonan et al., 2008; Melov et al., 2000; Mockett et al., 2010; Pérez et al., 2009; Tower, 2000) and therefore the role of oxidative stress in aging is still under debate. (3) The gene regulation theory of aging proposes that senescence occurs as a result of changes in gene expression (Kanungo, 1975; Weinert and Timiras, 2003). Studies have shown that mutations in the proteins associated with insulin/IGF-I signaling pathway can increase lifespan in yeast, worms, fruit flies and rodents probably by alterations in gene expression (Barbieri et al., 2003). (4) According to telomere theory, the telomere DNA located at the ends of eukaryotic chromosomes shortens with each cell division. When the telomeres reach a critical length, the cells stop replicating which eventually lead to death (Harley et al., 1992). (5) In 1989, Franceschi (Franceschi, 1989) proposed the immune theory of aging which suggests that aging is indirectly controlled by a network of cellular and molecular defense mechanisms. One of the

Involvement of several cellular events makes aging a complex process. Although, multiple theories of aging have been proposed to answer the questions, “why do we age” and “how do we age”, no single theory seems to be sufficient to provide a comprehensive explanation for aging. 2.1. Calcium hypothesis of aging Ca2+ hypothesis of aging has been proposed by Khachaturian in 1994 (Khachaturian, 1994) to explain the neurophysiological mechanisms involving Ca2+ signaling that are associated with aging and neurodegeneration. The main postulates of the hypothesis are as follows: The process of aging and neurodegeneration is a part of the continuum of molecular processes associated with development of nervous system, hence the same cellular mechanisms that regulate Ca2+ are also involved in the process of aging and neurodegeneration. The plasticity of the nervous system is regulated by a functional equilibrium between growth/regeneration and decay/degeneration processes. Mostly intracellular calcium concentration ([Ca2+]i) plays a key role in regulating the direction of this functional equilibrium. Also there is a systematic interaction between the extent of perturbation in [Ca2+]i and the duration of the deregulation (Kater et al., 1989). Therefore, any dysfunction in Ca2+ homeostasis can account for age related changes and associated diseases (Khachaturian, 1989a; Khachaturian et al., 1989b). There are several mechanisms by which regulation of [Ca2+]i can be disrupted, which are discussed in the section ‘Causes of Ca2+ dysregulation in aging brain’. These include changes in functioning of Ca2+ channels and alterations in the behavior of Ca2+ binding proteins, extrusion pumps, buffers and sequestration mechanisms (Arispe et al., 1993). Also, there could be many different antecedent factors like injury, toxins and free radicals which lead to disruptions in Ca2+ homeostasis. Depending on the cell type, the downstream consequence of altered calcium homeostasis can vary (Khachaturian, 1986). Thus, Ca2+ signaling plays a major role in the etiology of aging and age-associated neurological disorders. For the normal physiological activity, only a transient increase in the [Ca2+]i is required; however, in pathophysiological conditions related to aging, the ability to control Ca2+ overload is compromised. Since the levels of [Ca2+]i regulates cell survival and cell death mechanisms, any imbalance in this level can lead to many deleterious consequences. 2

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

Fig. 1. Calcium homeostasis mechanisms: Several Ca2+ channels and receptors present on the plasma membrane including VGCC, ligand-gated ion channels (LGICs) and mGluRs are activated in response to different stimuli like membrane depolarization and specific agonists like glutamate and glycine. Upon activation, these channels and receptors either mediate direct Ca2+ influx into the cytosol or activate second messenger-mediated intracellular signaling pathways involving Ca2+ release. Increase in [Ca2+]i beyond a threshold triggers the extrusion of Ca2+ out of the cell or into the intra-luminal space of ER or mitochondria. While, PMCA present on plasma membrane and SERCA present on ER extrude Ca2+ at the expense of ATP, Na+/Ca2+ antiporters (NCX, NCLX) perform the same using the energy stored in the electrochemical gradient of Na+. Mitochondrial Ca2+ uniporter (MCU) facilitates Ca2+ entry into the mitochondrial matrix where it drives ATP synthesis. Ca2+ from the ER can also enter the nucleus and can regulate gene expression.

of them are EF-hand family members (EF-hand corresponds to Ca2+coordinating helix-loop-helix structural motif) which includes parvalbumin, calmodulin (CaM), troponin C, calretinin, calcineurin (CaN), calbindin-D and S-100 protein. Ca2+ pumps present in plasma membrane and ER participate in regulating the [Ca2+]i by eliminating it from the cytoplasm (Fig. 1).

3. Neuronal calcium homeostasis Calcium is a messenger molecule that signals in a stimulus-dependent manner. Ca2+ is maintained at certain optimal concentrations in the cell (100 nM) and in the extracellular space (1.2 mM) (Gleichmann and Mattson, 2011) at the cost of energy and is critical for the functioning of regulatory mechanisms that allow Ca2+-induced signaling and prevent Ca2+-driven excitotoxicity. Ca2+ homeostasis is maintained with the participation of mitochondria and ER as well as the regulatory activities mediated by plasmalemmal Ca2+ channels including voltage-and ligand-gated Ca2+ channels (Fig. 1). These channels regulate neuronal excitation and electrogenesis. Ca2+ binding proteins also play a major role in homeostasis mechanisms (Fig. 1). They act as rapid buffering agents that decrease the peak [Ca2+]i. Some

3.1. Mitochondrial calcium buffering Mitochondrial buffering and energy homeostasis are highly interconnected events. Ca2+ acts as an indicator of energy demand. It neutralizes the negative membrane potential generated in the mitochondrial matrix as a result of pumping protons into the inter-membrane space happening during ATP production. In the condition of 3

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

higher energy demand, low ATP/ADP ratio and high [Ca2+]i increases the conductance of a mitochondrial calcium uniporter (MCU) which ensures unidirectional Ca2+ influx into the mitochondrial matrix. Within the matrix, increased Ca2+ concentration leads to activation of TCA cycle enzymes causing increased production of ATP and NADH (Denton, 2009). Recent reports also suggest the activation of MCU in response to nanomolar [Ca2+]i. Similarly, another antiporter, Letm1 (leucine zipper-EF-hand containing transmembrane region), located in the inner mitochondrial membrane is also involved in exchange of Ca2+ for H+ in a 1:1 stoichiometry (Santo-Domingo and Demaurex, 2010). Letm1 is essential for normal glucose metabolism and alters brain function in Wolf–Hirschhorn syndrome (Jiang et al., 2013). The increased Ca2+ from the mitochondrial matrix is pumped out through energy consuming pumps. Mitochondrial sodium calcium exchanger (NCLX) (Kim and Matsuoka, 2008), which efficiently mediates Li+/Ca2+ exchange as well as Na+/Ca2+ exchange, is activated under conditions where [Ca2+]i goes down to baseline levels and also when both ATP demand and oxygen consumption are low. NCLX extrudes one Ca2+ in exchange for three Na+ ions. The transient opening of the mitochondrial permeability transition pore (mPTP) (Hüser and Blatter, 1999) is also known to participate in clearing Ca2+ from mitochondrial matrix at the expense of ATP. All these pumps in conjunction with the uniporter and Letm1 act efficiently to maintain Ca2+ level according to the physiological needs (Rizzuto et al., 2000). Apart from the role of [Ca2+]i and matrix calcium concentration ([Ca2+]m), the levels of phosphate present in the extra- and intra-mitochondrial environments also play a key role in activating the Ca2+ influx and efflux mechanisms. Phosphate concentration within the mitochondria is maintained by phosphate transporter present on the inner mitochondrial membrane. The complex formed by phosphate inside the matrix with Ca2+acts as the storage form of Ca2+ which is readily dissociable. The ease of dissociation of this complex facilitates the regulation of the fine balance between activation of TCA cycle enzymes in the matrix and storage of the excess calcium (reviewed by Nicholls, 2005).

mitochondria is less, it can result in increased mitochondrial Ca2+ accumulation upon ER Ca2+ release (Csordás et al., 2006). Mitochondria associated ER membranes (MAMs) are areas where mitochondria and ER form specialized contacts that regulate the Ca2+ flux into mitochondria. MAMs consist of proteins like mitofusin, which help in making direct contacts between ER and mitochondria, and several other proteins involved in mitochondrial fission and fusion as well as organelle distribution. These areas are thought to take part in coordinating the high energy demand in response to a synaptic input with mitochondrial ATP synthesis. Microdomains of Ca2+ near the synaptic spines are transferred to areas near mitochondria. MAM proteins control the trafficking and subcellular localization of ER near to areas of high mitochondrial density where Ca2+ released from ER by CICR will be taken up by mitochondria through MCU (Kaufman and Malhotra, 2014; Vance, 2014). The calcium transporting mechanisms in the ER help in maintaining the [Ca2+]i. Most of the Ca2+ entering the ER is immobilized by calcium binding (storing) proteins that are having high capacity but, low binding affinity. Calsequestrin and calreticulin are among the proteins that bind and sequester intraluminal Ca2+ in a reversible manner, thereby buffering the excess Ca2+ in the ER as well as storing the Ca2+ (Milner et al., 1992). 3.3. Alterations in neuronal calcium homeostasis with age Even slight variations in the level of Ca2+ are lethal for neurons. As age increases, several changes occur at the physiological and molecular levels that affect the overall Ca2+ homeostasis in the neurons rendering them more susceptible to neurodegeneration (Fig. 2) (Kostyuk and Verkhratsky, 1994). Reports suggest an age dependent decrease in Ca2+ efflux which has been attributed to alterations in the ion exchange systems at plasma membrane and membranes of intracellular organelles (Erulkar and Fine, 1979), metabolic events and activity of Ca2+ sensors like CaM (Severson and Finch, 1981). Binding of Ca2+ to the plasma membrane as they pass through the plasmalemmal ion channels, termed superficial binding is already known (Hagiwara and Byerly, 1981). Age-associated changes in membrane dynamics as well as superficial binding of Ca2+ to plasma membrane can lead to decrease in Ca2+ uptake which in turn might lead to aberrant functioning of the neurons (Peterson and Gibson, 1983). Changes in expression level and activity of Ca2+ channels including voltage gated Ca2+ channels (VGCCs) (Campbell et al., 1996; Veng and Browning, 2002) as well as glutamate-gated ionotropic receptors such as N-methyl-D-aspartate receptors (NMDARs) (Bodhinathan et al., 2010; Lehohla et al., 2008) has also been reported with aging (Fig. 2). Alterations in Ca2+ release from RyRs on the ER have also been linked to aging associated Ca2+ dyshomeostasis (Gant et al., 2006). Decrease in the buffering capacity of SERCA (Murchison and Griffith, 1999) and plasma membrane Ca2+ ATPase (PMCA) (Michaelis et al., 1996) has been suggested to cause age related changes in Ca2+ transport leading to prolonged cytosolic Ca2+ increase. Also, diminished mitochondrial Ca2+ sink capability (Xiong et al., 2002) could lead to alteration in homeostasis of Ca2+. Thus, altered Ca2+ homeostasis as a result of age dependent changes in the Ca2+ transport mechanisms could lead to an overall net increase in the [Ca2+]i (Fig. 2).

3.2. Mechanisms of calcium homeostasis in ER Calcium homeostasis in ER is a complex process that can act through two mechanisms, calcium-induced calcium release (CICR) or store operated calcium entry (SOCE). CICR activation happens in response to small increase in [Ca2+]i which leads to direct activation of ryanodine receptors (RyRs) and/or IP3 receptors (IP3Rs) (via activation of phospholipase C that causes release of inositol-1,4,5- triphosphate, IP3). Upon activation, these receptors release Ca2+ from ER (Fig. 1). SOCE activation happens when a decrease in Ca2+ concentration in ER ([Ca2+]ER) is sensed by Stim (Stromal interaction molecules) 1 and 2. These proteins will bind to Orai channels at the plasma membrane and induce Ca2+ entry into the cytosol. Simultaneous activation of sarco/ endoplasmic reticulum Ca2+-ATPase (SERCA) on the ER membrane due to a low intraluminal Ca2+ concentration will ensure replenishment of Ca2+ inside the ER. CICR and SOCE mediated reciprocal stimulations are capable of generating periodic changes in Ca2+concentrations, which might also result in an increase in nuclear Ca2+concentration (reviewed by Bading, 2013) that can regulate gene expression (Mantamadiotis et al., 2002) (Fig. 1). Another mechanism involved in shaping the synapse in response to Ca2+ influx and the associated signaling is through the calpacitin family proteins, which in general prevent CaM from binding and activating Ca2+-CaM dependent kinases. A trigger at the synapse leading to sudden and steep increase in [Ca2+]i causes a conformational change in these proteins (in response to certain Ca2+ mediated phosphorylations and dephosphorylations), leading to release of CaM. CaM, thus released, further stimulates Ca2+-calmodulin dependent kinases and other proteins (Gerendasy, 1999). It has been reported that if the distance between ER and

3.4. Glial calcium homeostasis and age associated alterations Glial cells play an important role in the maintenance and modulation of neuronal structure and functions. For a long time, Ca2+ mediated signal transduction was thought to be absent in glial cells until reports suggested the occurrence of Ca2+ currents in response to electrical stimulation (Roitbak, 1970). Although the basic scheme of Ca2+homeostasis in glia remains the same as in case of neurons or any 4

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

Fig. 2. Calcium signaling in healthy and aging brain: In normal conditions, Ca2+ levels are tightly regulated whereas in aging brain Ca2+ dysregulation occurs. Upon activation, NMDAR and VGCC mediate Ca2+ influx into cytosol whereas mGluRs stimulates the release of Ca2+ through intracellular receptors like RyRs and IP3Rs present on ER. AMPAR containing GluR2 subunit (GluR2+) conduct Na+ and are impermeable to Ca2+. The cytosolic Ca2+ level is buffered by cellular Ca2+ binding proteins (CBPs) (e.g. calmodulin, calbindin, parvalbumin etc), and SERCA pump, which uptakes Ca2+ into ER. During Ca2+ homeostasis, mitochondria function normally to meet cellular energy demands. Upon aging, there are structural changes associated with mitochondria in addition to hypofunction of NMDAR and increased activity of L-type VGCC. AMPAR lacking GluR2 subunit (GluR2-) can also permeate Ca2+ along with other receptors. Reduced Ca2+ buffering by CBPs, altered SERCA pump, abnormal Ca2+ efflux from intracellular Ca2+ stores and mitochondrial dysfunction disturb Ca2+ homeostasis. Under pathological conditions like AD and PD, Ca2+ can also enter the cell through pores formed by α-synuclein/Ab peptide resulting in Ca2+ dysregulation which leads to cognitive decline and/or neurodegeneration.

Nedergaard, 1994). Evidence for the co-expression of AMPA and kainate receptors in oligodendrocytes is also available (Gallo et al., 1994; Patneau et al., 1994). Ca2+ influx through the AMPA and kainate receptors has, in turn, been linked to regulation of gene expression (Liu and Almazan, 1995; Pende et al., 1994). In case of glia, ER acts as major Ca2+ storing intracellular organelle (Gambetti et al., 1975; Privat et al., 1995). Uptake of Ca2+ into ER involves Ca2+ pumps. Most of the intracellular Ca2+ release in response to neurotransmitters or neurohormones occurs through IP3Rs (Berridge, 1993) in both astrocytes (Khodakhah and Ogden, 1993) and oligodendrocytes (Dent et al., 1996). Expression of RyR in glial cells and the CICR induced through RyR are controversial. Plasmalemmal Ca2+ permeability is another

other cell type, differences exist in the expression profiles of several crucial molecules involved in Ca2+ regulation. The expression of several membrane channels and receptors that participate in generation of Ca2+ mediated signals in these cells were reported (Deitmer et al., 1998). Expression of VGCCs has been reported in Schwann cells, oligodendrocytes and astrocytes (Kirischuk et al., 1995; Newman, 1985; Robitaille et al., 1996). Expression of functional AMPA/kainate receptors, in astrocyte cultures has been reported by several groups (reviewed by Verkhratsky and Steinhäuser, 2000). The GluR-induced changes in Ca2+ concentration further induce signaling within the glial network (Bezzi et al., 1998), leading to further elevation of Ca2+ levels in the neighbouring neurons (Araque et al., 1998; 5

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

factor regulated by the Ca2+ bound to the intracellular stores. A drop in the [Ca2+]i is compensated by Ca2+ influx through SOCC (Golovina, 2005). Expression of Na+-Ca2+ exchanger (NCX) has been reported in astrocytes which regulate the ionic content in the interstitium. During an electrical excitation, neuronal activity leads to decreased levels of Na+ and Ca2+ in the intercellular space (Benninger et al., 1980). This decrease is reversed by the surrounding astrocytes. Intracellular Ca2+ sensors play a major role by acting as rapid buffers and integrating the signaling mechanisms. All these proteins come together for maintaining Ca2+ homeostasis within glia. Physiological aging has mostly been correlated with neuronal loss but only recently have the changes in the neuroglia been taken into account. Reports have revealed decrease in the number, density, distribution and morphology of astrocyte, oligodendrocytes and microglia with age (Cerbai et al., 2012; Peters and Sethares, 2004; Rodríguez et al., 2014; Streit and Xue, 2013; Tremblay et al., 2012). Contradictory to these reports, Gomez-Gonzalo et al. (Gómez‐Gonzalo et al., 2017) reported that the astrocyte-neuron signaling remains unaltered in aged brain. Since the major role of neuroglial cells is to support and nurse the neurons, an age-dependent alteration in the number of these cells might have a significant role in altering neuronal Ca2+ homoeostasis with age. Density of receptor-mediated currents shows an age-dependent change. The expression of functional NMDA receptors and ionotropic purinergic receptors (P2X) in glial cells have been reported to increase several times in old mice but the Ca2+ currents mediated through these receptors seemed to decline (Lalo et al., 2011). Such changes in the glial cells further lead to altered functioning of neurons in the brain. Together, the altered signaling in neurons and neuroglial cells lead to agedependent changes in the overall brain functioning.

electron transport chain (ETC) in the mitochondria can alter Ca2+ homeostasis, thereby resulting in cell-type specific molecular pathologies observed in neurodegenerative diseases (Lin and Beal, 2006). Mitochondrial dysfunction and subsequent alteration in Ca2+ homeostasis is a consequence of the following causative events: (i) Mitochondrial DNA (mtDNA) mutations: mtDNA in the aging brain is highly susceptible to mutations, owing to limited repair mechanisms (Cline, 2012), lack of protection by histone proteins and its close proximity to the inner mitochondrial membrane where reactive oxygen species (ROS) are generated (Mecocci et al., 1993). Large-scale deletions (Corral-Debrinski et al., 1992) and point mutations (Lin et al., 2002) in mtDNA occur either during replication (Park and Larsson, 2011) or during repair of damaged mtDNA (Krishnan et al., 2008). Studies carried out using ‘mtDNAmutator’ mouse model (Kujoth et al., 2005; Trifunovic et al., 2004), a strain in which the mtDNA polymerase-γ (POLG) is deficient of its 3′-5′ exonuclease (proofreading) activity, have shown a positive correlation between accumulation of mutations in mtDNA and deteriorating mitochondrial function resulting in accelerated aging (Trifunovic, 2006). (ii) ROS production and oxidative stress: Mitochondrial respiration generates ROS in the cell. In mature neurons, tight regulation of neuronal NADPH oxidases (enzymes involved in ROS production) (Sorce and Krause, 2009) and antioxidant defense mechanisms, coupled with astrocytes (Baxter and Hardingham, 2016) can combat free radical-mediated oxidative damage of macromolecules like nucleic acids, proteins and lipids (Chakravarti and Chakravarti, 2006; Evans et al., 2004; Montine et al., 2002). However, in senescent neurons, an increase in ROS production (Sawada and Carlson, 1987; Sasaki et al., 2010) with a consequent increase in oxidative stress (Floyd and Hensley, 2002; Gemma et al., 2007), combined with increased sensitivity of genes to oxidative damage and deficiency in repair mechanisms (Lin and Beal, 2006), can affect the activity of Ca2+-dependent kinases/phosphatases and Ca2+ conducting channels, thereby disrupting normal physiological Ca2+ signaling pathways (Ermak and Davies, 2002). Lu et al. (Lu et al., 2004) showed an age-dependent alteration of gene expression by transcriptome profiling of the human frontal cortex. Genes encoding for proteins involved in synaptic plasticity, vesicular/protein transport and mitochondrial function, that also participate in synaptic Ca2+ signaling were down regulated with age due to increased oxidative stress. This is attributed to the increased sensitivity of GC-rich sequences in the promoter region of these genes to oxidative damage and to lack of transcription-coupled repair at these regions (Lu et al., 2004; Tu et al., 1996). Mitochondrial Ca2+ ions can also regulate ROS production by activating nitric oxide synthase (NOS) (Feissner et al., 2009). (iii) Metabolic stress: Decreased levels of glucose transporters in the brain with aging can cause glucose hypometabolism, deficits in glucose utilization and insufficient ATP thereby causing metabolic stress to neuronal cells (Camandola and Mattson, 2017). Moreover, with advancing age, the mitochondria lose its ability to generate ATP due to decrease in activity of enzymes involved in TCA cycle and ETC (Bubber et al., 2005; Sheehan et al., 1997) and due to increased free radical induced interruption of oxidative phosphorylation (Schulz et al., 1997). Impaired cellular energy metabolism compromises the ability of neurons to regulate cellular Ca2+ levels and dynamics by inhibiting energy-dependent Ca2+ efflux/sequestration (Gleichmann and Mattson, 2011), thereby rendering them vulnerable to excitotoxic damage (Beal, 1992). (iv) Morphological changes and ultrastructural abnormalities: Age-related alterations in mitochondrial membrane fluidity (Daum, 1985) can affect the activity of the respiratory chain (Kwong and Sohal, 2000). Structural changes in mitochondria such as swelling

4. Causes of Ca2+ dysregulation in aging brain The primary/major cause of dysregulation in neuronal Ca2+ signaling network during aging can be attributed to mitochondrial dysfunction, de-regulation in Ca2+ channel activity, alterations in levels of Ca2+ binding proteins and ER stress. 4.1. Major causes 4.1.1. Mitochondrial dysfunction The role of impaired mitochondrial function in the etiology of ageassociated neurodegenerative diseases has been studied and reviewed extensively (Boveris and Navarro, 2008; Lin and Beal, 2006). The normal functioning of the brain demands high energy, which is provided by mitochondria. Therefore, age-related disruptions in mitochondrial functions can adversely affect brain activity. In neuronal Ca2+ signaling, mitochondria play multiple roles (Zündorf and Reiser, 2011). (a) It buffers Ca2+ level fluctuations at the soma and synaptic terminals; the change of Ca2+ accumulated from cytosol into the mitochondrial matrix can influence cell survival and death (Nicholls, 2005). (b) The activity of Ca2+-sensitive dehydrogenases such as FAD-dependent glycerol-3-phosphate dehydrogenase (G3PDH) (a component of the glycerol-phosphate shuttle present on the outer surface of the inner mitochondrial membrane), pyruvate dehydrogenase, NAD+-isocitrate dehydrogenase and α-ketoglutarate dehydrogenase, which are enzymes involved in the citric acid cycle present in the mitochondrial matrix, can regulate ATP synthesis (Denton, 2009). (c) Its highly dynamic fission/fusion processes can regulate the propagation of Ca2+ signals within the cell (Frieden et al., 2004). During aging, disruption in tricarboxylic acid (TCA) cycle and 6

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

conditions (Bezprozvanny, 2009, 2010; Lin and Beal, 2006). Mutations in mtDNA have also been associated with AD (Corral-Debrinski et al., 1994), PD (Kraytsberg et al., 2006), HD (Horton et al., 1995) and ALS (Dhaliwal and Grewal, 2000).

(Fig. 2), vacuolization, reduction in cristae, aggregation of mutant proteins like Cu/Zn-superoxide dismutase (SOD1) and intramitochondrial inclusion bodies have been reported in the pathogenesis of sporadic AD, sporadic PD and ALS (Jaiswal, 2014; Lin and Beal, 2006; Trimmer et al., 2000). Such anomalies can alter mitochondrial membrane potential (Hagen et al., 1997) thereby disrupting its Ca2+ buffering capacity (Zündorf and Reiser, 2011).

4.2.2. Disease-related accumulation of proteins Pathological accumulation of hyperphosphorylated, misfolded or mutant proteins such as Aβ oligomers and neurofibrillary tangles (NFTs) in AD, α-synuclein in PD, SOD1 in ALS and huntingtin in HD at extracellular/intracellular/intramitochondrial spaces can increase intracellular Ca2+ overload in the following ways (Bezprozvanny 2009, 2010):

4.1.2. De-regulation of Ca2+ channel activity In specific regions of the aged brain, various subunits and subtypes of cell surface Ca2+ channels such as NMDAR and VGCCs are differentially expressed and regulated by posttranslational modifications and ROS (Kumar et al., 2009). ROS is also responsible for redox regulation of intracellular Ca2+ ion channels, pumps and exchangers − RyR and IP3R are stimulated by oxidation, SERCA and PMCA are inhibited by oxidation and NCX is modulated by oxidation (Feissner et al., 2009). Thus, age-related modifications in the activity of Ca2+ transport systems can deregulate Ca2+ homeostasis upon aging (Kumar et al., 2009).

(a) Increase the activity of Ca2+ channels like IP3R, RyR, NMDAR, VGCC, Ca2+-permeable AMPAR and modulate the function of SERCA (b) Aβ oligomers and α-synuclein aggregates can form Ca2+-permeable pores in the plasma membrane and thus facilitate the intracellular entry of Ca2+ (c) Reduce the levels of CBPs and thereby decrease Ca2+-buffering capacity in neuronal cytosol

4.1.3. Alterations in levels of Ca2+ binding proteins (CBPs) Intracellular Ca2+ concentrations are also regulated by CBPs present in cytosol (for e.g. calbindin D-28k, calretinin, parvalbumin) and ER (for e.g. calreticulin, calnexin) (Baimbridge et al., 1992). The buffering capacity of these proteins renders neurons resistant to glutamate and oxidative stress-induced degeneration, both of which involve excessive elevations of intracellular Ca2+ (Hugon et al., 1996; Mattson et al., 1991). During brain aging, region-specific decrease in expression levels of calbindin D-28k and calretinin (Bu et al., 2003; Iacopino and Christakos, 1990) can lead to failure of intraneuronal Ca2+ homeostasis that finally culminates in neuronal death.

4.2.3. De-regulation by non-neuronal cells Non-neuronal cells like astrocytes and microglia can also indirectly regulate neuronal Ca2+ signaling. Impaired glutamate re-uptake due to selective loss of excitatory amino acid transporter 2 (EAAT2) on astrocyte surface upon aging (Simpson et al., 2010) can increase NMDAR stimulation and neuronal Ca2+ overload thereby decreasing the neuroprotective capacity of astrocytes (Pertusa et al., 2007). Activation of microglia concurrent with neuroinflammation and/or neurodegeneration, increases the release of soluble factors like D-serine, a coagonist of NMDAR (Wu and Barger, 2004; Wu et al., 2004), which can potentiate NMDA receptor-mediated currents (Hayashi et al., 2006) and destabilize Ca2+ signaling. With age, however, a decrease in D-serine immunoreactivity was reported in the hippocampus and cortex of rats which may influence NMDA receptor-mediated cortical function (Williams et al., 2006).

4.1.4. Endoplasmic reticulum (ER) stress Apart from mitochondria, the ER also plays a vital role in maintaining Ca2+ homeostasis majorly through its physical and functional association with the mitochondria (Csordás et al., 2006). The ER contains Ca2+-dependent chaperone proteins which aid proper protein folding and subsequent post translational modifications (Kim et al., 2008). With advancing age, an increase in ROS-mediated modification of ER Ca2+ channels (like IP3R, RyR, SERCA) (Feissner et al., 2009) and chaperone proteins (like calreticulin) can cause Ca2+ depletion from ER (Verkhratsky, 2005) and impair protein folding (Chaudhari et al., 2014). Accumulation of misfolded proteins triggers ER stress and activates the UPR. However, age-related structural changes in ER (Hinds and McNelly, 1978) together with a decline in the effectiveness of UPR components, chaperone proteins and enzymes can exacerbate misfolding and accumulation of misfolded proteins in the cell (Brown and Naidoo, 2012; Taylor, 2016). The exposed hydrophobic residues of misfolded proteins incorporate into the cell membrane to destabilize it and impair intracellular redox status by forming ion channels, thereby resulting in destabilization of Ca2+ homeostasis and finally apoptosis (Kourie and Henry, 2002). Besides the primary causes mentioned above, the following secondary factors can also contribute to the risk of Ca2+ dysregulation upon brain aging.

4.2.4. Lysosomal dysfunction Lynch and Bi (Lynch and Bi, 2003) proposed a model linking mitochondrial ROS production and lysosomal dysfunction with Ca2+ leakage from ER in the aging brain. Disruption in the endosomal/lysosomal proteolytic pathway due to oxidative damage of lysosomal membrane during aging, can lead to the release of partially degraded intralysosomal material (called lipofuscins) and cathepsins D and E (Nakanishi et al., 1997) along with intralysosomal Ca2+ into the cytosol (Appelqvist et al., 2013). Progressive accumulation of lipofuscins with age (Terman and Brunk, 1998), cause elevated ER and oxidative stress (Wei et al., 2008), resulting in Ca2+ depletion from ER by ROS-mediated modification of ER-based Ca2+ channels (Görlach et al., 2006; Lynch and Bi, 2003). 4.2.5. Human immunodeficiency virus (HIV) infection The HIV-infected aging population is highly susceptible to neuronal Ca2+ dysregulation and neurotoxicity caused by the viral coat protein gp120 and the transcription regulator protein, Tat (Haughey and Mattson, 2002; Nath, 2002). Tat directly induces neuronal apoptosis by a mechanism involving increase in [Ca2+]i, mediated through IP3R and NMDAR, mitochondrial Ca2+ uptake and ROS production, and caspase activation (Haughey et al., 1999; Haughey and Mattson, 2002; Kruman et al., 1998). Interaction of Tat and gp120 with astrocytes and microglia release excitotoxins, cytokines and nitric oxide, which can further aggravate direct toxic effects of Tat and gp120 on neurons (Haughey and Mattson, 2002).

4.2. Minor causes 4.2.1. Genetic factors Familial cases of AD, PD, HD and ALS are characterized by inherited mutations in the genomic DNA that predisposes the individual with a high risk of developing these diseases as they progress with age. Mutations in genes that code for proteins/enzymes involved in neuronal growth and repair, synaptic transmission, protein degradation, apoptosis, ROS-scavenging and normal mitochondrial function can either directly or indirectly, cause Ca2+ dysregulation in these diseased 7

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

promotes CREB dephosphorylation, resulting in synaptic loss. Similarly in AD neuropathology also, a decrease in the level of phosphorylation of CREB at Ser133 has been observed (Alberini, 2009; Kamat et al., 2016). Mechanistic basis of this signaling might be the extra-synaptic NMDAR mediated nuclear accumulation of a protein called Jacob. When it localizes to the nucleus, it causes CREB dephosphorylation and decreased expression of BDNF (Dieterich et al., 2008; Karpova et al., 2013). Inactivation of ERK1/ 2 by extra-synaptic NMDAR and regulation of CREB activity might be another mechanism which affects the cell survival pathway (Hetman and Kharebava, 2006). (b) FOXO activation: Increased extrasynaptic NMDAR activity stimulates the import of pro-death signaling proteins, the forkhead box O class of transcription factors (FOXO), into the nucleus where it promotes the transcription of pro-death genes resulting in excitotoxic cell death (Hardingham and Bading, 2010). (c) Calpain activation: Excessive Ca2+ entry through extrasynaptic NMDAR activates calpain which cleaves striatal enriched tyrosine phosphatase (STEP61) and the cleaved form of STEP cannot interact with its normal substrate, resulting in the activation of p38 mitogen-activated protein kinase (MAPK), a pro-death signaling protein (p38 MAPK was negatively regulated by STEP). Activation of p38 induced by chronic NMDA or glutamate exposure can cause death in cerebellar granule cells and cortical neurons (Kawasaki et al., 1997; Xu et al., 2009).

4.2.6. Hormonal imbalance Aging is also associated with changes in various hormonal levels. An increase in VGCC activity, particularly L-type Ca2+ channels (LTCCs), has been correlated to age-dependent alterations in stress hormones such as glucocorticoids (GCs) (Kerr et al., 1992; Landfield and Eldridge, 1994), and sex hormones, such as estrogen (Brewer et al., 2009) and testosterone (Thibault and Landfield, 1996). Neuroactive steroids like 17β-estradiol can block the elevation of [Ca2+]i (Kawahara and Kuroda, 2001), most likely by directly modulating the activity of PMCA (Żylińska et al., 1999). 4.2.7. Environmental and lifestyle factors ROS production and oxidative damage leading to Ca2+ dysregulation can also result from the response of the body to different environmental stimuli such as inflammation and tissue injury (Mittal et al., 2014), hyperoxia (Dean et al., 2004), chemotherapeutics (Kovacic and Osuna, 2000), UV (McMillan et al., 2008), chemical oxidants (Klaunig et al., 2011) and toxic metals (Ercal et al., 2001). Sleep deprivation during aging can also lead to impaired ER stress response activation (Naidoo et al., 2008). Physical and psychological stress accumulated over an individual’s lifetime can also induce oxidative damage via imbalances in hormones, neurotransmitters and oxidants, factors that are known to alter Ca2+ homeostasis, and thus result in accelerated brain aging (Liu and Mori, 1999). 5. Mechanisms of cell death induced by Ca2+

Neuronal death can be mediated through any of the known pathways such as apoptosis, necrosis and autophagy. The initial trigger for death can be the same for all pathways, but each pathway is associated with different sets of hallmark events. Apoptosis is the most studied form of neuronal death. In mammals, two apoptotic pathways are described: mitochondrial or the intrinsic pathway and the death receptor or the extrinsic pathway (Earnshaw et al., 1999; Green and Kroemer, 2004). Caspases are key players of apoptosis (Troy and Salvesen, 2002). In neurons, Caspase-3 mediates apoptosis and also participates in neurogenesis and synaptic plasticity. Apoptosis is characterized by cell membrane blebbing, cell shrinkage, chromatin condensation and nuclear fragmentation (Kerr et al., 1972). The cell disintegrates forming the apoptotic bodies which are engulfed by phagocytes. Therefore, inflammatory response is not seen in apoptosis. Necrosis is another mode of neuronal death. It results in the breakdown of plasma membrane and leakage of the cytosol which leads to inflammatory response and spreading of death signals to adjacent cells. It is the major mode of death in hypoxia, ischemia and seizures and its mechanism in neurons is poorly understood. It appears that there are no clear boundaries differentiating neuronal apoptosis and necrosis. Necrosis shares the steps of the intrinsic pathway of apoptosis (Niquet et al., 2006). Neurons mainly use the intrinsic pathway of apoptosis for cell death (Martin-Villalba et al., 1999). Major proteins of intrinsic pathway are the Bcl-2 family of proteins, both pro- (Bax and Bak) and anti-apoptotic (Bcl-2, Bcl-XL, etc.). Bax and Bak cause mitochondrial outer membrane permeabilization. Excitotoxicity and DNA damage or any external stress in neurons can activate proteins such as cyclin-dependent and stress−activated kinases, p53 and the DNA-dependent protein kinase, ataxia telangiectasia mutated (ATM). These can further activate anti- or pro-apoptotic pathways resulting in cell survival or cell death, respectively (Nikoletopoulou et al., 2013). Anti-apoptotic members (Bcl-2) which are present in the outer membrane of mitochondria counteract the effect of pro-apoptotic factors and can retain the mitochondrial membrane integrity. Bax and Bak cause the release of cytochrome c to cytoplasm and induce the formation of apoptosome complex. Apoptosome binds and activates pro-caspase 9. While remaining attached to the complex, caspase-9 activates caspase-3/caspase-7. Ca2+ overload in cells can activate apoptosis and necrosis pathways (Rothstein, 1996). The GluN2B subunit of NMDAR interacts with proteins like DAPK1 (death associated protein kinase 1), postsynaptic

During development and maturation, fine-tuning of the balance between cell death and survival is essential for maintaining the functional and structural integrity of neural networks. Nearly half of the neurons are lost during development by the process of programmed cell death (PCD) (D'amelio et al., 2010). Increase in intracellular Ca2+ is a central feature associated with neuronal death. The chief mediators of Ca2+ influx in neurons are NMDARs, AMPA receptors (AMPARs), Acid sensing ion channels (ASIC), Transient receptor potential (TRP) channels (TRPV1, TRPM2, TRPM7, etc) and VGCCs (Artal-Sanz and Tavernarakis, 2005; Gees et al., 2010). Detailed description on Ca2+ conducting channels is included in the following sections. The excitatory neurotransmitter glutamate acts through its receptors on the postsynaptic neuron, such as ionotropic receptors and metabotropic receptors. Ionotropic receptors are ligand-gated cation channels such as NMDAR, AMPAR and kainate receptors. Excessive activation of glutamate receptors can lead to dysregulation of Ca2+ homeostasis, generation of free radicals, activation of NOS and apoptotic pathways (Wong et al., 2002) ultimately leading to cell death by the process termed excitotoxicity. Excitotoxicity is the major cell death mechanism in neurodegeneration and in the aged brain (Chohan and Iqbal, 2006). Oxygen/glucose deprivation can cause prolonged depolarization of postsynaptic neurons due to lack of ATP needed to bring the neurons back to resting state. This can lead to sustained release of excitatory neurotransmitter, glutamate. This results in over activation of AMPARs and NMDARs and subsequent activation of VGCC and hence Ca2+ overload, triggering neuronal death (Choi, 1992., Fern and Möller, 2000). Excessive intracellular Ca2+ activates phospholipases, endonucleases and Ca2+-sensitive proteases such as calpains which lead to organelle and membrane breakdown and cleavage of enzymes involved in neuronal signaling pathways (Vosler et al., 2008). Excitotoxic insults can also lead to oxidative stress, protein misfolding and mitochondrial dysfunction (Malkus et al., 2009). Accumulation of all these can cause secondary release of Ca2+ and activation of cell death pathways. NMDARs are distributed both in synapses and in extrasynaptic regions. Extrasynaptic NMDARs are thought to play major role in excitotoxicity which is mediated by the following mechanisms: (a) CREB shut off pathway: Extra-synaptic NMDAR activation 8

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

substrates of caspases. Mutations in the genes taking part in autophagy cause neurodegeneration. Caspase inhibition and enhancement of autophagy could be potential strategies to prevent or alleviate the deleterious events associated with aging and neurodegeneration.

density-95 (PSD-95) and SREBP-1 (sterol regulatory element-binding protein-1) (Nikoletopoulou et al., 2013; Taghibiglou et al., 2009). Interaction of GluN2B with DAPK and SREBP-1 might lead to induction of apoptosis mediated by extrinsic pathway in the neurons (Taghibiglou et al., 2009). Age-related neuronal loss is primarily due to apoptosis. This is characterized by an increased DNA fragmentation rate in aged versus young rats (Fujino et al., 1996). DNA fragmentation is observed in hippocampus, frontal cortex and basal forebrain of old rats (Taglialatela et al., 1996). About 50-fold less apoptosis was observed in normal age matched controls as compared with brains from AD patients. Aβ, PS-1 and PS-2 mutations can induce apoptosis in neurons (Araki et al., 2001; Ethell and Buhler, 2003; Zeng et al., 2015). PS1 and PS2 are important for calcium signaling (Guo et al., 1997). Aβ can cause ROS generation (Schilling and Eder, 2011). Pro-apoptotic Bax mRNA levels are upregulated and levels of the anti-apoptotic Bcl-2 are downregulated in human ALS tissues (Mu et al., 1996; Troost et al., 2005). Also, cells with mutant Huntingtin proteins may be more susceptible to apoptosis induced by aging associated oxidative stress (Beal, 1995). Different subpopulations of hippocampal neurons can respond to the same insult differently. In lithium-pilocarpine model of epilepsy, cell death in the CA1 pyramidal layer was mediated by necrosis while death in the inner granule cell layer was mediated by apoptosis. How neurons distinguish between these two modes of death is not clear. One reason appears to be the difference in neuronal maturity. It appears that the less mature neurons undergo apoptotic death and more differentiated or the adult neurons are prone to necrotic pathway (LopezMeraz et al., 2010). Changes in intracellular Ca2+ can trigger apoptosis (Orrenius et al., 2003). Release of Ca2+ from ER can lead to cytochrome c release from mitochondria and caspase activation. This is implicated in pathologies such as AD and stroke (Rao et al., 2004). Huntingtin, amyloid precursor protein (APP), Parkin, presenilins 1 and 2 are cleaved by caspase-3 (Kahns et al., 2002). There is a significant increase in the synaptic procaspase-3 and active caspase-3 levels in AD patients as compared with the age-matched controls. Synapse degeneration is also caused by caspase-3 (Louneva et al., 2008). Caspase-3 might cause loss of synapses and cognitive decline in such patients (Scheff et al., 2007). It is known that cell death in substantia nigra of PD patients is mediated by Caspase-3 (Hartmann et al., 2000). Caspase-3 inhibitors (M-826) reduce cell death after striatal lesions in adult rats (Toulmond et al., 2004). Autophagy is mainly (Levine and Yuan, 2005) a cellular recycling process (Yoshimori, 2007). It is devoid of any inflammatory response. It mainly helps in organellar quality control and its increase is often related to longevity. It prevents apoptosis and necrosis by restoring the cells from injury. Also, induction of autophagy causes release of Bcl-2 and FLIP (FLICE-like inhibitory protein) which block the apoptotic pathways. The faulty proteins reach lysosomes by distinct mechanisms consisting of delivery within the endosomes and autophagosomes. The steps involved in autophagy are substrate sequestration and autophagosome formation, substrate recognition and selective autophagy and lysosomal digestion of autophagic substrates. Mutations in the genes associated with these steps lead to neurodegeneration. SQSTM1 (p62) is involved in substrate recognition and selective autophagy and its mutations are associated with ALS. Mutations in Dynactin is also implicated in the pathophysiology of ALS. Mutations in VCP (p97) lead to frontotemporal dementia and PINK and parkin protein mutations can cause PD (Nixon, 2013). It is known that increased autophagy can delay the process of aging. Activation of autophagy by rapamycin, rapalogs and valproate reduces the toxic aggregation of proteins in animal models of HD (Ravikumar et al., 2010). Neurons are terminally differentiated cells which do not have the capacity to divide. Hence the loss of neurons cost significantly to an organism. In such a context, it is beneficial to understand the mechanisms of neuronal death associated with neurodegeneration and aging. Many of the proteins expressed during neurodegeneration are

6. Age-associated changes in calcium conducting channels and receptors A variety of Ca2+ channels and receptors are involved in neuronal Ca2+ signaling. These include extracellular receptors such as NMDAR, VGCC, AMPAR, metabotropic glutamate receptor (mGluR), transient receptor potential (TRP) cation channels like TRPV1, TRPM2 and TRPM7, ASIC, P2X and intracellular receptors such as IP3R and RyR. These receptors undergo age-related changes in their expression and activity which can disrupt Ca2+ homeostasis and cause decline in normal brain functions such as cognitive impairment and motor dysfunction (Kumar et al., 2009). The following sections briefly discuss the normal functions and age-associated alterations of these receptors. 6.1. NMDAR NMDAR mainly found in the hippocampus and cerebral cortex (Cotman et al., 1989), plays an important role in regulating synaptic plasticity that underlies learning and memory (Collingridge, 1987; Lisman et al., 1998). The receptor is a heterotetrameric protein complex composed of three different types of subunits – GluN1, GluN2A-D and GluN3A-B (Monyer and Sprengel, 1992). NMDARs are vulnerable to changes with age. Age-associated decline in NMDAR function is observed mainly in CA1-CA3 regions of hippocampus and in prefrontal cortex, the brain regions mainly involved in learning and memory, in aged animals. This may contribute to cognitive impairment in elderly population (Barnes et al., 1997; Eckles-Smith et al., 2000; Liu et al., 2008; Magnusson, 1998; Zhao et al., 2009). Functional decline in NMDARs with age can be attributed to the following factors: Alterations in the subunit composition and expression: One of the main reasons for age-related NMDAR hypofunction is the altered expression of its subunits (Magnusson, 2000). Decrease in the mRNA and protein of GluN1 has been reported in the aged hippocampus (Adams et al., 2001; Eckles-Smith et al., 2000; Liu et al., 2008) as well as in other brain regions (Gore et al., 2002; Magnusson et al., 2005). However, contradicting reports have shown no age-related alterations in GluN1 protein expression in the hippocampus (Zhao et al., 2009). Decrease in the mRNA and protein of GluN2A and GluN2B were also observed in the hippocampus (Adams et al., 2001; Liu et al., 2004b, 2008; Magnusson, 2001; Sonntag et al., 2000; Zhao et al., 2009). Contradicting to these findings, few studies showed no significant changes in the expression of GluN2A protein in the hippocampus (Villayandre et al., 2004) and cortex (Sonntag et al., 2000) and GluN2B protein in the frontal cortex (Sonntag et al., 2000). A study carried out on aged macaque monkeys showed decreased GluN2B mRNA levels in the frontal cortices, but not in the hippocampus (Bai et al., 2004). Similarly, decreased levels of protein and mRNA of GluN1 and GluN2B in hippocampus and cortex of postmortem AD brain has also been observed (Mishizen-Eberz et al., 2004). Expression levels of GluN2C and GluN2D were not altered significantly with age (Magnusson, 2012) while limited studies have been carried out to determine changes in GluN3A and GluN3B. Therefore, age related cognitive decline can be attributed to alterations in the expression levels of GluN2A and GluN2B subunits (Magnusson, 1998, 2001). Apart from subunit expression, variations in subunit composition upon aging can also contribute to functional alterations of NMDAR. High levels of GluN2B containing NMDARs have been shown to be beneficial for efficient learning during aging in animal models (Cao et al., 2007). An increase in the ratio of GluN2A/GluN2B subunits upon aging can modulate the magnitude of Ca2+ signal, which occurs as a result of faster deactivation kinetics and 9

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

lower Ca2+ conducting capacity of GluN2A compared to GluN2B (Magnusson, 2012; Vicini et al., 1998). Receptor localization: The role of GluN2B localization in spatial long-term memory in aged brain was studied by Zhao et al. (Zhao et al., 2009) and Zamzow et al. (Zamzow et al., 2013). NMDARs are located at both synaptic and extrasynaptic sites on neurons. Alterations in NMDAR localization can affect its function during aging. Poor memory in aged animals is correlated to low expression of GluN2B subunit in the synaptic membrane fraction of the frontal cortex and hippocampus (Zhao et al., 2009) and also to an increase in PSD-95/GluN2B ratio in aged frontal cortex (Zamzow et al., 2013). Phosphatase activity: Age-associated functional decline in NMDAR activity can also be explained by a shift in the balance between kinase and phosphatase activities. NMDAR channel functions are highly influenced by phosphorylation of its C-terminal tail. The phosphorylation state of GluN1 and GluN2 subunits can regulate surface expression and localization of the receptor (Chung et al., 2004; Lin et al., 2006). Increased phosphatase activity is favored during aging (Norris et al., 1998) which can lead to internalization of NMDA receptors thereby resulting in hypofunction (Snyder et al., 2005). Oxidative stress: NMDAR function, expression and trafficking can also be influenced by age associated increase in oxidative stress. Oxidation and reduction of sulfhydryl moieties alter receptor function. An oxidative environment can decrease NMDAR function in neuronal cell cultures (Aizenman et al., 1989; Aizenman, 1995; Sucher and Lipton, 1991) owing to the formation of disulfide bonds on the sulfhydryl group-containing amino acid residues in the receptor (Aizenman et al., 1990; Choi et al., 2001; Sullivan et al., 1994). On the other hand, NMDAR can also mediate excitotoxic cell death. GluN2B containing extrasynaptic NMDARs play a major role in excitotoxicity by initiating neuronal death signaling cascades as explained in Section 5, leading to neuronal loss that underlies neurodegeneration. The interaction of disease related proteins such as HTT, tau, Aβ and parkin with NMDARs can modulate its activity. This has been discussed under Section 7.

et al., 2007; Thibault et al., 2001). L-type VGCC on the other hand promotes neuronal survival by activating Ca2+-dependent neuroprotective genes (Bading et al., 1993; Dolmetsch et al., 2001; West et al., 2001). Hence any dysregulation in its activity can affect the neuronal health. 6.3. AMPAR AMPARs are ligand-gated ion channels composed of combinations of four separate subunits (GluA1-4). Glutamate induces an increase in the concentration of cytoplasmic Ca2+ by directly activating AMPA and NMDA receptor channels and by indirectly activating VGCC. Accordingly, antagonists of AMPARs, NMDARs or VGCC have been reported to be effective in protecting central nervous system (CNS) neurons against glutamate-mediated excitotoxic neuronal death (Mattson, 2003; Weiss et al., 1990). Aβ oligomers that participate in AD pathogenesis can form Ca2+ permeable channels in membranes (Arispe et al., 1993). Aβ oligomers also affect neuronal Ca2+ homeostasis by modulating the activity of AMPARs (Hsieh et al., 2006) along with NMDARs (De Felice et al., 2007), and P/Q-type VGCCs (Nimmrich et al., 2008). Motor neurons (MNs) express a high proportion of Ca2+ permeable AMPARs, which lack the GluR2 subunit (Fig. 2) (Hollmann et al., 1991; Sommer et al., 1991). Ca2+ influx through AMPAR channels has been implicated in motor neuron damage in ALS (Tateno et al., 2004). Pharmacological inhibition of AMPARs protected MNs from damage induced by activated microglia in co-culture experiments (Zhao et al., 2004). In contrast to activated microglia, astrocytes have a largely protective role in ALS excitotoxicity. Astrocytes appear to upregulate the expression of GluR2 subunits in MNs through the action of released factors, which reduces AMPAR-mediated Ca2+ influx (Van Damme et al., 2007). This mechanism could be targeted for neuroprotection in pathological conditions involving neurodegeneration due to hyperactivity of AMPAR. 6.4. mGluRs

6.2. VGCC

Metabotropic glutamate receptor, mGluR5 subtype, is abundant in the adult hippocampus and cerebral cortex (Romano et al., 1996) and is involved in the maintenance of synaptic plasticity (Bortolotto et al., 2005; Manahan-Vaughan and Braunewell, 2005; Neyman and Manahan-Vaughan, 2008). It is shown that mice lacking mGluR5 exhibit impaired learning and reduced long term potentiation (LTP) in the CA1 region (Lu et al., 1997). While NMDAR dependent synaptic plasticity is correlated with cognitive functions in adult rats, NMDAR-independent LTP and long term depression (LTD) were shown to be linked to cognitive performances in aged rats (Boric et al., 2008; Lee et al., 2005). mGluRs play a significant role in NMDAR-independent synaptic plasticity (Manahan-Vaughan, 1997). The stimulation of both mGluR1 and mGluR5 triggers the release of Ca2+ from intracellular stores which in turn can facilitate the hyperphosphorylation of tau by up-regulating protein kinase activities (Tsai et al., 2005). In an AD animal model with reduced presenilin function, age-related cognitive deficits were prevented by knockdown of mGluR via pharmacological or genetic methods (McBride et al., 2010). Synaptic plasticity deficits including age-dependent enhancement in mGluR-LTD and cognitive deficits can be reversed by chronic in vivo treatment with mGluR antagonists. Since a similar over activation of mGluR occurs in Fragile X Syndrome mouse model, mGluR antagonist treatment alleviates the disease phenotype in the model (Choi et al., 2011).

Increase in age is related to enhanced VGCC expression and activity (Fig. 2) in CA1 hippocampal neurons (Thibault and Landfield, 1996), increase in slow after hyperpolarization and reduced neuronal excitability (Disterhoft et al., 1996). It has been shown that these changes in VGCC are involved in age related cognitive deficits (Thibault and Landfield, 1996) which can be prevented by treatment with VGCC inhibitor nimodipine (Batuecas et al., 1998; Moyer et al., 1992; Thompson et al., 1990). L-type VGCC inhibitor improves cognition in both young and old rats (Ingram et al., 1994; Levy et al., 1991), and it is associated with reduced prevalence of AD (Anekonda and Quinn, 2011). Nimodipine treatment has shown improvements over placebotreated patients on several cognitive measures (Tollefson, 1990). Dopaminergic (DA) neurons from old mice exhibit smaller L-type Ca2+ channel currents (Branch et al., 2014). This in turn contributes to reduced DA neuron firing which could play a role in age-related decrements in dopamine-mediated signaling and its behavioral consequences such as decreased voluntary movements in case of PD. In fact there are reports that Ca2+-channel blocker usage in humans decreases the incidence of PD (Becker et al., 2008) and administration of isradipine, a VGCC inhibitor, reduces oxidative damage to DA neurons in a mouse model of PD (Ilijic et al., 2011). VGCC generally does not cause neuronal death. It has been shown that neuronal vulnerability depends on extent of Ca2+ loading but does not appear to depend explicitly on the route of Ca2+ entry (Stanika et al., 2012). VGCC can promote neurodegeneration if their density and activity is increased (Stanika et al., 2012) as it happens in advanced age. The enhanced L-type current caused by aging leads to Ca2+ dependent synaptic depression and cognitive impairment (Fig. 2) (Brewer

6.5. TRPV1, TRPM2 and TRPM7 Transient receptor potential melastatin 2 (TRPM2) and transient receptor potential vanilloid 1 (TRPV1) are Ca2+ permeable nonselective cation channels that are responsive to oxidative stress (Nazıroğlu, 2012). Extracellular homocysteine (Hcy) concentrations are 10

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

6.8. Intracellular receptors (RyR and IP3Rs)

frequently increased in the elderly. Hcy causes elevated oxidative stress and induction of tau polymerizations, which may have a very important role in the etiology of AD and dementia (Baydas et al., 2003; Stipanuk, 2004). Increased oxidative stress can bring about apoptosis through activation of oxidative stress-dependent TRPM2 and TRPV1 cation channels in the hippocampal neurons (Nazıroğlu et al., 2014; Tjiattas et al., 2004). Ca2+ influx through channels such as TRPM2, TRPV1, VGCC and NMDAR, triggered by neuronal activity, causes mitochondrial depolarization. It has been shown that blockers of the TRPV1 [capzapine (CPZ)], the TRPM2 [2-aminoethoxydiphenyl borate (2APB)] and VGCC (verapamil + diltiazem) prevented D,L-buthionineS,R-sulfoximine (BSO) and Hcy-induced increase in intracellular Ca2+. Similarly, another TRPM2 channel blocker, N-(p-amyl cinnamoyl) anthranilic acid (ACA), an NMDAR Ca2+ channel blocker, MK-801 and antioxidant glutathione (GSH) attenuated the intracellular Ca2+ increase (Övey and Naziroğlu, 2015). It was further suggested that cytosolic GSH levels and elevated Hcy may act as TRPM2 and TRPV1 channel regulators in diseases of hippocampal neurons (Övey and Naziroğlu, 2015). TRPM7 is a Ca2+ permeable cation channel and plays a major role in Ca2+ and magnesium homeostasis and in early embryonic development (Jin et al., 2012; Sun et al., 2015). TRPM7 is composed of an ion channel and a protein kinase. Under physiological conditions, TRPM7 is weakly permeable to calcium, magnesium and some of the trace ions. The channel activity is regulated by the extracellular Mg2+ concentration (Ryazanova et al., 2010). TRPM7 is activated by reactive oxygen and nitrogen species. Excessive ROS production associated with aging and neurodegenerative diseases such as AD and PD (Behl, 1997; Nunomura et al., 2007) might activate TRPM7 and induce increase in intracellular calcium (Nadler et al., 2001; Sun et al., 2015). Magnesium deficiency in animals leads to increased susceptibility to methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced toxicity (Muroyama et al., 2009). Neurons in substantia nigra (SN) express TRPM7 channels. Magnesium deficiency because of decreased functional TRPM7 channels may be contributing to the loss of SN neurons in PD patients (Cook et al., 2009; Oyanagi et al., 2006).

The RyRs are a family of Ca2+ release channels. It is a homotetramer and there are three subtypes of RyRs in mammalian tissues: RyR1-3 (Sorrentino and Volpe, 1993). The primary trigger for RyR opening is Ca2+ itself, the same ion it permeates. Aging is associated with increased oxidative stress that could influence the highly redox sensitive RyR (Bull et al., 2008; Hidalgo et al., 2004; Huddleston et al., 2008). A decrease in the excitability of CA1 pyramidal neurons contributes to the age related decrease in hippocampal function and memory decline. Decreased neuronal excitability in aged neurons can be observed as an increase in the Ca2+-activated K+-mediated post burst after hyperpolarization (AHP). It is shown that slow component of AHP (sAHP) in aged CA1 neurons (aged-sAHP) is decreased by 50% upon application of the reducing agent dithiothreitol (DTT) (Bodhinathan et al., 2010). The effect of DTT on the aged-sAHP was blocked following depletion of intracellular Ca2+ stores (ICS) by thapsigargin or blockade of RyRs by ryanodine, but not by inhibition of L-type voltage gated Ca2+ channels (L-type VGCC), inhibition of Ser/ Thr kinases or inhibition of the large conductance Big potassium (BK) channels, suggesting that the age-related increase in the sAHP was due to release of Ca2+ from ICS through redox sensitive RyRs (Bodhinathan et al., 2010). Reversal of the redox state of aged hippocampal CA1 pyramidal neurons is a potential strategy to ameliorate Ca2+ dysregulation and prevent the increase in sAHP, which restore normal functionality in aged neurons (Bodhinathan et al., 2010). It has been shown that poor performance in Morris water maze (MWM) correlated with increased RyR expression in aged rats and RyR antagonist dantrolene rescued age-associated spatial memory deficits in aged rats (Hopp et al., 2014) and in a transgenic mouse model of AD (Chakroborty et al., 2012). Alterations in RyR-mediated Ca2+ signaling are associated to AD etiopathogenesis by means of various mechanisms, including the regulation of Aβ amyloid production, synaptic function, memory and learning abilities and neuronal death (Alberdi et al., 2013). RyR expression is also altered in patients with AD and mild cognitive impairment (Bruno et al., 2012). Deletion of RyR3 in the AD APP/PS-1 transgenic mouse model improved neuronal function in older mice (Liu et al., 2014). In aged rats, reducing RyR function would be beneficial to memory performance by reducing the sAHP, while in young rats this would blunt RyR-mediated amplification of NMDAR signaling (Lei et al., 1992). RyR-dependent alterations in Ca2+ handling is a major factor in aging and AD and may be a relevant target for treatment or prevention of these conditions (Hopp et al., 2014). IP3Rs are homo/heterotetrametric intracellular Ca2+ release channels composed of four subunits and like RyRs three forms of IP3Rs (IP3R1-3) are known (Nakagawa et al., 1991). The involvement of IP3Rs and RyRs in neurodegenerative diseases relies on abnormal Ca2+ signaling that ultimately leads to excitotoxicity in specific areas of the CNS (Takei et al., 1994). It is shown that cytotoxicity of Aβ oligomers involves Ca2+ release from the ER via activation of IP3Rs, as demonstrated in vitro in Xenopus oocytes (Demuro and Parker, 2013). Similarly, studies in fibroblasts isolated from patients with familial AD revealed that presenilins activate IP3Rs potentiating Ca2+ release from the ER (Ito et al., 1994). Abnormal Ca2+ homeostasis in AD is further amplified by the increased Aβ production caused by IP3R activation (Cheung et al., 2008; Shilling et al., 2014). Mutant Huntingtin is shown to bind and activate IP3R1. It is also shown to interact with mitochondrial membrane and impair mitochondrial function (Tang et al., 2003). Similarly, the exogenous expression of the mutant human huntingtin in Drosophila melanogaster led to retinal degeneration, which was prevented by knocking-down IP3R1 (Kaltenbach et al., 2007).

6.6. ASIC ASICs are nonselective ion channels which open in response to acidic pH. They are composed of six different subunits which vary in their response to pH. ASICs are mainly implicated in conditions such as ischemia (Zha, 2013). Ca2+ influx through GluN2B-containing NMDA receptors can activate Ca2+/CaM dependent protein kinase II (CaMKII), which phosphorylates ASIC1a channel at Ser478 and Ser479 leading to enhanced Ca2+ influx through these channels and ultimately death of the neuron (Chu and Xiong, 2013). It appears that excessive NMDAR activation and neuronal death in neurodegenerative diseases is mediated through secondary Ca2+ influx through ASICs. 6.7. P2X receptors P2X receptors are activated by nucleotides and nucleosides and induce fast excitatory responses (Coddou et al., 2011; Fields and Stevens, 2000). ATP released by neurons and glia in an activity-dependent manner (Chakfe et al., 2002) further activates P2X receptors. These channels also conduct Ca2+ and are implicated in several neurodegenerative diseases. Purines are released from healthy as well as dead cells into the extracellular space. Purines released might also activate P2X receptors causing calcium influx and lead to secondary Ca2+ influx into cytosol by VGCC activation (Apolloni et al., 2009). Under in vivo conditions, hippocampal damage after ischemia is associated with up-regulation of P2X2 and P2X4 receptors (Cavaliere et al., 2003). There is reduction in P2X receptor expression upon aging (Burnstock and Dale, 2015).

7. Ca2+ signaling in the diseased brain cells The neuronal system is extremely sensitive to changes in [Ca2+]i. There is a range of molecular components from kinases, phosphatases 11

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

hypothesized that mutations in PS-1 (Stutzmann et al., 2006) can indirectly increase the expression of RyR (Chan et al., 2000; Rybalchenko et al., 2008) and IP3R (Cheung et al., 2008) thus leading to overdose of Ca2+ release into the cytosol from the ER making the neuron further vulnerable to oxidative stress and excitotoxicity (Mattson et al., 2000b). Another major reason for increased susceptibility of aging brain to AD is the decreased Ca2+ buffering capacity in the aged neurons. The cortical and hippocampal neurons are compromised due to decreased levels of CBPs. It is also reported that there is an activation of Ca2+dependent protease, calpain, which cleaves various proteins required for the normal functioning of neurons, hence resulting in apoptosis (Bezprozvanny, 2010).

and adenylate cyclases to different transcription factors like CREB that are sensitive to Ca2+ signals. Minute perturbations and abnormalities in Ca2+ levels occur during aging and consequently the downstream mechanisms will also undergo corresponding changes. However, major fluctuations in Ca2+ homeostasis might lead to neurological and neurodegenerative diseases. Most neurodegenerative diseases occur predominantly in the aged population. Aging-associated cellular and molecular alterations in the brain may trigger the onset of neurodegeneration and impaired signaling mechanisms as seen in AD, PD, HD and ALS. 7.1. Neuronal Ca2+ signaling in AD

7.2. Neuronal Ca2+ signaling in HD

AD is an age-related neurodegenerative disorder characterized by progressive memory loss. This disorder is mostly sporadic but familial AD is also prevalent. A mutation in the genes encoding APP, PS-1 or PS2 can cause accumulation of Aβ peptides and NFTs. In AD pathogenesis, accumulation of Aβ peptides can cause Ca2+ dysregulation in cortical and hippocampal neurons. Aβ oligomers can form Ca2+-permeable channels on the plasma membrane (Fig. 2), which are observed majorly in the vicinity of amyloid plaques (Arispe et al., 1993; Shankar et al., 2007). These oligomers can associate with phosphatidylserine (PtdS), which translocates to the outer leaflet of the plasma membrane with age-related increase in mitochondrial dysfunction. This induces pore formation and thereby enhances Ca2+ influx leading to cell death (Lee et al., 2002). Aβ is also known to generate ROS, mainly hydrogen peroxide and hydroxyl radicals which induce membrane associated oxidative stress (MAOS) like membrane lipid peroxidation to produce an aldehyde, 4-hydroxy-2,3-nonenal (HNE). HNE can bind to cysteine, lysine and histidine residues of membrane proteins and impair the function of ion-motive ATPases like Na+/K+ and Ca2+ATPases, the neuronal glucose transporter, GLUT3 and the astrocyte glutamate transporter, GLT-1 (Blanc et al., 1998; Hensley et al., 1994; Keller et al., 1997; Mark et al., 1997). This further increases [Ca2+]i, making the neurons more prone to excitotoxicity and apoptosis. High [Ca2+]i induced by Aβ plaques can cause the axons to loose their morphology and function, which is reversed with FK-506, an inhibitor of the Ca2+/CaMdependent phosphatase, CaN, indicating the role of CaN, in AD-related atrophy (Kuchibhotla et al., 2008). Aβ oligomers can also alter Ca2+ homeostasis by modulating NMDAR, AMPAR and P/Q-type VGCC activities (Nimmrich et al., 2008). NMDAR-associated disturbances in Ca2+ homeostasis have been implicated in Aβ-mediated cognitive deficit and neuronal degeneration in AD neuropathology. Aβ can impair NMDAR-mediated LTP in several ways by (a) desensitization of NMDAR by activation of CaN (Chen et al., 2002; Danysz and Parsons 2012), (b) enhancement of NMDAR internalization (Hoey et al., 2009), (c) overactivation of NMDARs (Hu et al., 2009; Li et al., 2011), (d) activation of calpain and the subsequent degradation of dynamin 1 (a protein involved in synaptic vesicle recycling) (Kelly and Ferreira, 2006) and (e) reducing dendritic spine density (Shankar et al., 2007). Aβ and tau proteins can also induce excitotoxicity by activating GluN2B containing NMDARs, which was prevented by ifenprodil, a selective GluN2B antagonist (Amadoro et al., 2006). Aβ can also induce glutamate release from astrocytes, which in turn activates extrasynaptic NMDARs in neurons, resulting in neuronal death (Talantova et al., 2013). Apart from all these, SNPs in the NMDAR subunit genes have been associated with the pathophysiology of AD. A missense mutation in the coding region of GRIN2B has been found in the brains of AD patients suggesting a close relationship between mutations in GluN2B subunit and alteration in synaptic functioning (Andreoli et al., 2014). Mutations in PS can also cause destabilization of Ca2+ signaling pathways (Leissring et al., 2000; Yoo et al., 2000). Reports suggest that mutant PS functions as Ca2+ leak channels in the ER (Nelson et al., 2007; Tu et al., 2006), thus causing ER stress which in turn culminates in synaptic loss and axonal degeneration (Salminen et al., 2009). It is

HD is an age-related genetic neurodegenerative disorder characterized by an expansion of repeated CAG (glutamine) motif in the huntingtin (HTT) protein because of a single mutation in the HTT gene (Gusella and MacDonald, 2000). The medium spiny neurons (MSN) in the striatum are majorly affected in HD. Mitochondrial dysfunction due to disruption of ETC, excessive free radical production and the consequent accumulation of mtDNA mutations results in Ca2+ overload in the MSN of HD patients (Bezprozvanny, 2010). Studies on HD patients and animal models showed sequential changes in the expression levels of Ca2+-signaling proteins in the brain (Kuhn et al., 2007). The mutated HTT protein (HTTexp) can cause dysregulation of Ca2+ signaling in MSNs by modulating the activity of Ca2+ channels and receptors. HTTexp increases the affinity of IP3R1 for IP3 thereby increasing Ca2+ release from ER into cytosol (Tang et al., 2003). HTTexp toxicity also affects glutamate-induced Ca2+ signaling in MSNs by increasing the activity of GluN2B containing NMDARs, thus making the neurons highly susceptible to excitotoxicity (Fan et al., 2007; Zeron et al., 2002). Inhibiting NMDAR using drugs like memantine and riluzole has neuroprotective effect in a mouse MSN culture model of HD (Shehadeh et al., 2006). Calpain activation mediated through mGluR1/5 and GluN2B containing NMDAR can also contribute to Ca2+ toxicity in HD (Gafni et al., 2004). Therefore, destabilizing the influence of HTTexp with glutamate receptors and IP3R1 has a protective effect on striatal MSN both in vitro and in vivo (Tang et al., 2009). HTTexp also modulates VGCC activity by binding to α2/δ subunit (Kaltenbach et al., 2007) and CaV2.2 pore forming subunit of VGCC (Swayne et al., 2005). 7.3. Neuronal Ca2+ signaling in PD PD is an age-related neurodegenerative disorder that affects the dopaminergic neurons (DA) in the substantia nigra pars compacta (SNc). Due to their increased sensitivity to Ca2+, the SNc DA neurons are at higher risk for age-related cell death. There is a strong correlation between mitochondrial dysfunction and PD (Henchcliffe and Beal, 2008; Vila et al., 2008). Inhibitors of Complex I in ETC such as MPTP, rotenone and paraquat have been shown to cause Parkinsonian characteristics (Betarbet et al., 2000; Przedborski et al., 2004). Postmortem PD brain samples showed a decrease in Complex I activity in the SNc region which could lead to mitochondria derived oxidative stress such as ROS production, decrease in ATP levels and also in excitotoxicity (Mann et al., 1994). The genes mutated in PD such as parkin, PINK1 and DJ-1 can also affect mitochondrial homeostasis and Ca2+ regulation (Scarffe et al., 2014). Mutant parkin is reported to play a role in ER-mitochondria crosstalk that influences Ca2+ regulation, thus affecting cellular homeostasis (Calì et al., 2013). PINK1 regulates mitochondrial Ca2+ efflux via NCLX and therefore its deficiency, in PD, leads to Ca2+ overload in mitochondria thus resulting in oxidative stress (Gandhi et al., 2009). DJ-1 is thought to play an important role in protecting DA neurons against Ca2+ induced stress by regulating mitochondrial 12

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

Table 1 Recently developed drug molecules that reached the clinical trials against neurodegenerative diseases. Drug

Target

Disease

Status

Effect

MEM-1003 EVT-101 Memantine Dimebon

Ca2+ channel antagonist GluN2B NMDAR NMDAR antagonist Mitochondria

AD AD AD AD/HD

Improves memory and learning Improves cognitive function Improves cognitive function Moderate effect on cognitive function

Riluzole Edaravone Namzaric (memantine + donepezil)

Blocks NMDAR and Na+ channels (glutamate antagonist) Decreases oxidative stress Memantine: NMDAR antagonist Donepezil: Inhibit acetylcholine esterase

ALS ALS AD

Discontinued Discontinued Approved, Investigational Investigational Under clinical trials Approved, Investigational Approved Approved

Increases the lifespan Slows the rate of disease progression Reduces moderate to severe dementia

can help in implementing better strategies for neuroprotection. Preventative measures can also be taken in diet and lifestyle for healthy aging.

uncoupling proteins. Decrease in DJ-1 levels decreases the levels of mitochondrial uncoupling proteins, thus increasing the Ca2+ induced stress. The proteins associated with familial PD such as α-synuclein and LRRK2 cause dysregulation in autophagy/lysosomal degradation process. Mutant LRRK2 shows deficits in regulating Ca2+ homeostasis, by affecting mitophagy, mitochondrial membrane potential and by increasing mtDNA mutations. It was shown that L-type Ca2+ channel inhibitors could prevent such events inside the cell (Bezprozvanny, 2010). Alterations in the expression pattern of NMDAR subunits and their phosphorylation status have also been linked to the progression of PD (Hallett and Standaert, 2004). Reports on experimental PD animal models suggest that inhibiting the glutamatergic neurotransmission can decrease motor disabilities associated with PD (Murray et al., 2002).

7.5. Drugs targeting calcium signaling and mitochondria for neurodegenerative disorders Discovering drugs for neurodegenerative disease have always been challenging as the mechanisms of such diseases are still unclear. Until now there have been several drugs in clinical trials directed towards a plethora of targets including calcium signaling, dopaminergic pathway, mitochondria and cholinergic pathway (Table 1). A major drawback with many such drugs has been reduced efficacy and presence of side effects. These drugs generally bring about only temporary relief of disease symptoms or aid in decreasing the progression of the disease (Muir, 2006). Mining for drugs targeting calcium signaling and mitochondria in neurodegenerative disorders have gained importance since they are known to have a prominent role in the pathogenesis of these diseases (Chaturvedi and Beal, 2008). Dimenbon is a well-known antihistamine drug but it was found to have a neuroprotective effect when it was used in picomolar concentration and is still under investigation. NMDAR have always been a pharmacological target for many years. Treatments with NMDAR antagonists were majorly tested in stroke, traumatic brain injury and also in PD, HD, AD and epilepsy (Bezprozvanny, 2010). NMDAR antagonists have major side effects psychotomimetic effects like psychosis and sympathomimetic effects like hypertension - thus limiting their doses in clinical trials. High affinity uncompetitive antagonist and competitive antagonist showed profound side effects whereas lower affinity antagonists such as memantine have been more successful as therapeutic agents (Table 1) as it does not exhibit major side effects (Muir, 2006). Thus, there are several issues that need to be addressed in the future to find NMDAR targeted drugs with more specificity, long term efficacy and lesser side effects. Developing novel drugs against targets such as ER leak channels or MCU appear to hold promise (Bezprozvanny, 2009). Combination therapy using drugs targeting different molecules can also be used for such complex disorders. The relevant information regarding the drug molecules are extracted from Drug bank (https://www.drugbank.ca/), ALZFORUM (http://www.alzforum.org/) and from Bezprozvanny (Bezprozvanny, 2009).

7.4. Neuronal Ca2+ signaling in ALS ALS is an aging-associated neurodegenerative disorder in which there is a progressive loss of motor neurons in the spinal cord and brain. The degenerating motor neurons exhibit dysfunction in mitochondrial mechanisms, Ca2+ homeostasis, organelle transport and dynamics (Bacman et al., 2006; Hervias et al., 2006; Magrané and Manfredi, 2009; Shi et al., 2010). Mutation in SOD1, an antioxidant enzyme, is one of the most common cause of familial ALS (fALS). Mutant SOD1 causes dysfunction in mitochondria and proteasome, enhances free radical production, decreases ATP production, causes aggregation of proteins, causes neurofilament dysregulation, impairs axonal transport and also causes glutamate-induced excitotoxicity (Pasinelli and Brown, 2006; Rothstein, 2009). Mutant SOD1 is also reported to accumulate in ER (Kikuchi et al., 2006; Urushitani et al., 2006) and mitochondrial membranes (Liu et al., 2004a) and this might cause abnormal Ca2+ signaling. Mutant SOD1 expressing glial cells lead to acceleration of disease progression (Boillée et al., 2006; Yamanaka et al., 2008). It is also observed that glutamate receptor overactivation plays a major role in elevation of [Ca2+]i in ALS (Rothstein, 1996). AMPARmediated Ca2+ influx might cause misfolding and aggregation of SOD1 (Tateno et al., 2004). Beers et al. reported that overexpression of parvalbumin, a Ca2+ binding protein, protects the motor neurons and delays the onset of the disease in Cu/Zn-SOD mutant mice (Beers et al., 2001). A genome wide association study in ALS patients identified IP3R2 gene (ITPR2) as a candidate susceptibility gene, which has a main role in maintaining [Ca2+]i (Garber, 2008; Van Es et al., 2007). There has also been a report that the ALS patients possess immunoglobulins (IgGs) directed against VGCCs and the titer of the antibodies is proportional to disease progression (Delbono et al., 1991, 1993) Ca2+signaling proteins and mitochondrial Ca2+ signaling system play a major role in neurodegenerative disorders and hence these can be promising targets for the treatment of such disorders. There are several ongoing or recent clinical trials for AD, PD, ALS and HD with Ca2+signaling blockers and mitochondrial stabilizers (Bezprozvanny, 2010). In the future, new drugs that can target and stabilize neuronal Ca2+ homeostasis are likely to be developed. Also, a thorough understanding of the cellular and molecular mechanisms of these disorders

8. Conclusions While there are several systems and mechanisms that regulate cellular Ca2+ signaling in the brain, impairments in any component might lead to major dyshomeostasis of Ca2+ resulting in immediate phenotypes such as cognitive decline as well as long term phenotypes such as neurodegeneration. Despite the available data, a complete understanding of the maintenance mechanisms supporting Ca2+ homeostasis is still lacking. Impaired calcium signaling has been linked to brain aging. The impairments are augmented under conditions of age-associated neurodegenerative diseases. Data on the role of channels, 13

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

transporters and binding proteins in Ca2+ homeostasis will help in using these proteins as therapeutic targets. Considering the strong association between Ca2+ dyshomeostasis and brain aging, discovery of anti-aging drugs could be envisaged by targeting Ca2+ homeostasis, in addition to drug development against neurodegenerative diseases. Promoting healthy aging of the brain is of immense significance in public health and also has socio-economic importance.

Baimbridge, K.G., Celio, M.R., Rogers, J.H., 1992. Calcium-binding proteins in the nervous system. Trends Neurosci. 15 (8), 303–308. Barbieri, M., Bonafè, M., Franceschi, C., Paolisso, G., 2003. Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. Am. J. Physiol. Endocrinol. Metab. 285 (5), E1064–E1071. Barnes, C.A., Rao, G., Shen, J., 1997. Age-related decrease in the N-methyl-D-aspartate Rmediated excitatory postsynaptic potential in hippocampal region CA1. Neurobiol. Aging 18 (4), 445–452. Batuecas, A., Pereira, R., Centeno, C., Pulido, J.A., Hernández, M., Bollati, A., Bogónez, E., Satrústegui, J., 1998. Effects of chronic nimodipine on working memory of old rats in relation to defects in synaptosomal calcium homeostasis. Eur. J. Pharmacol. 350 (2), 141–150. Baxter, P.S., Hardingham, G.E., 2016. Adaptive regulation of the brain’s antioxidant defences by neurons and astrocytes. Free Radic. Biol. Med. 100, 147–152. Baydas, G., Kutlu, S., Naziroglu, M., Canpolat, S., Sandal, S., Ozcan, M., Kelestimur, H., 2003. Inhibitory effects of melatonin on neural lipid peroxidation induced by intracerebroventricularly administered homocysteine. J. Pineal Res. 34 (1), 36–39. Beal, M.F., 1992. Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann. Neurol. 31 (2), 119–130. Beal, M.F., 1995. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann. Neurol. 38 (3), 357–366. Becker, C., Jick, S.S., Meier, C.R., 2008. Use of antihypertensives and the risk of Parkinson disease. Neurology 70 (16 Part 2), 1438–1444. Beers, D.R., Ho, B.K., Siklós, L., Alexianu, M.E., Mosier, D.R., Mohamed, A.H., Otsuka, Y., Kozovska, M.E., McAlhany, R.E., Smith, R.G., Appel, S.H., 2001. Parvalbumin overexpression alters immune‐mediated increases in intracellular calcium, and delays disease onset in a transgenic model of familial amyotrophic lateral sclerosis. J. Neurochem. 79 (3), 499–509. Behl, C., 1997. Amyloid β-protein toxicity and oxidative stress in Alzheimer’s disease. Cell Tissue Res. 290 (3), 471–480. Benninger, C., Kadis, J., Prince, D.A., 1980. Extracellular calcium and potassium changes in hippocampal slices. Brain Res. 187 (1), 165–182. Berridge, M.J., 1993. Inositol trisphosphate and calcium signaling. Nature 361, 315–325. Berridge, M.J., 1998. Neuronal calcium signaling. Neuron 21 (1), 13–26. Betarbet, R., Sherer, T.B., MacKenzie, G., Garcia-Osuna, M., Panov, A.V., Greenamyre, J.T., 2000. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3 (12), 1301–1306. Bezprozvanny, I., 2009. Calcium signaling and neurodegenerative diseases. Trends Mol. Med. 15 (3), 89–100. Bezprozvanny, I.B., 2010. Calcium signaling and neurodegeneration. acta naturae. Acta Naturae (англоязычная версия) 1 (4). Bezzi, P., Carmignoto, G., Pasti, L., Vesce, S., Rossi, D., Rizzini, B.L., Pozzan, T., Volterra, A., 1998. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391 (6664), 281–285. Bjorksten, J., 1968. The cross linkage theory of aging. J. Am. Geriatr. Soc. 16 (4), 408–427. Blanc, E.M., Bruce‐Keller, A.J., Mattson, M.P., 1998. Astrocytic gap junctional communication decreases neuronal vulnerability to oxidative Stress-induced disruption of Ca2+ homeostasis and cell death. J. Neurochem. 70 (3), 958–970. Bodhinathan, K., Kumar, A., Foster, T.C., 2010. Redox sensitive calcium stores underlie enhanced after hyperpolarization of aged neurons: role for ryanodine receptor mediated calcium signaling. J. Neurophysiol. 104 (5), 2586–2593. Boillée, S., Yamanaka, K., Lobsiger, C.S., Copeland, N.G., Jenkins, N.A., Kassiotis, G., Kollias, G., Cleveland, D.W., 2006. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312 (5778), 1389–1392. Boric, K., Muñoz, P., Gallagher, M., Kirkwood, A., 2008. Potential adaptive function for altered long-term potentiation mechanisms in aging hippocampus. J. Neurosci. 28 (32), 8034–8039. Bortolotto, Z.A., Collett, V.J., Conquet, F., Jia, Z., van der Putten, H., Collingridge, G.L., 2005. The regulation of hippocampal LTP by the molecular switch, a form of metaplasticity: requires mGlu 5 receptors. Neuropharmacology 49, 13–25. Boveris, A., Navarro, A., 2008. Brain mitochondrial dysfunction in aging. IUBMB Life 60 (5), 308–314. Branch, S.Y., Sharma, R., Beckstead, M.J., 2014. Aging decreases L-type calcium channel currents and pacemaker firing fidelity in substantia nigra dopamine neurons. J. Neurosci. 34 (28), 9310–9318. Brewer, L.D., Thibault, O., Staton, J., Thibault, V., Rogers, J.T., Garcia-Ramos, G., Kraner, S., Landfield, P.W., Porter, N.M., 2007. Increased vulnerability of hippocampal neurons with age in culture: temporal association with increases in NMDA receptor current, NR2A subunit expression and recruitment of L-type calcium channels. Brain Res. 1151, 20–31. Brewer, L.D., Dowling, A.L., Curran-Rauhut, M.A., Landfield, P.W., Porter, N.M., Blalock, E.M., 2009. Estradiol reverses a calcium-related biomarker of brain aging in female rats. J. Neurosci. 29 (19), 6058–6067. Brown, M.K., Naidoo, N., 2012. The endoplasmic reticulum stress response in aging and age-related diseases. Front. Physiol. 3. Bruno, A.M., Huang, J.Y., Bennett, D.A., Marr, R.A., Hastings, M.L., Stutzmann, G.E., 2012. Altered ryanodine receptor expression in mild cognitive impairment and Alzheimer's disease. Neurobiol. Aging 33 (5) pp.1001-e1. Bu, J., Sathyendra, V., Nagykery, N., Geula, C., 2003. Age-related changes in calbindin-D 28k, calretinin, and parvalbumin-immunoreactive neurons in the human cerebral cortex. Exp. Neurol. 182 (1), 220–231. Bubber, P., Haroutunian, V., Fisch, G., Blass, J.P., Gibson, G.E., 2005. Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann. Neurol. 57 (5), 695–703. Bull, R., Finkelstein, J.P., Gálvez, J., Sánchez, G., Donoso, P., Behrens, M.I., Hidalgo, C.,

Acknowledgements The authors acknowledge Arunkumar, R. C. for suggestions. Financial support from Rajiv Gandhi Centre for Biotechnology (RGCB), Government of India (GOI) and Indian Council of Medical Research (ICMR), GOI are gratefully acknowledged. RC received fellowship from ICMR. MK received fellowship from Kerala State Council for Science, Technology and Environment (KSCSTE), Government of Kerala, India. LK received fellowship from Council of Scientific and Industrial Research (CSIR), GOI. RSJ and SG received fellowships from Department of Science and Technology (DST), GOI. SL received fellowship from Department of Biotechnology (DBT), GOI. References Adams, M.M., Morrison, J.H., Gore, A.C., 2001. N-methyl-D-aspartate receptor mRNA levels change during reproductive senescence in the hippocampus of female rats. Exp. Neurol. 170 (1), 171–179. Aizenman, E., Lipton, S.A., Loring, R.H., 1989. Selective modulation of NMDA responses by reduction and oxidation. Neuron 2 (3), 1257–1263. Aizenman, E., Hartnett, K.A., Reynoldst, I.J., 1990. Oxygen free radicals regulate NMDA receptor function via a redox modulatory site. Neuron 5 (6), 841–846. Aizenman, E., 1995. Modulation of N-methyl-D-aspartate receptors by hydroxyl radicals in rat cortical neurons in vitro. Neurosci. Lett. 189 (1), 57–59. Alberdi, E., Wyssenbach, A., Alberdi, M., Sánchez‐Gómez, M., Cavaliere, F., Rodríguez, J.J., Verkhratsky, A., Matute, C., 2013. Ca2+‐dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease. Aging Cell 12 (2), 292–302. Alberini, C.M., 2009. Transcription factors in long-term memory and synaptic plasticity. Physiol. Rev. 89 (1), 121–145. Alzheimer's Association, 2016. 2016 Alzheimer's disease facts and figures. Alzheimer's Dement. 12 (4), 459–509. Amadoro, G., Ciotti, M.T., Costanzi, M., Cestari, V., Calissano, P., Canu, N., 2006. NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation. Proc. Natl. Acad. Sci. U. S. A. 103 (8), 2892–2897. Andreoli, V., De Marco, E.V., Trecroci, F., Cittadella, R., Di Palma, G., Gambardella, A., 2014. Potential involvement of GRIN2B encoding the NMDA receptor subunit NR2B in the spectrum of Alzheimer’s disease. J. Neural Transm. 121 (5), 533–542. Anekonda, T.S., Quinn, J.F., 2011. Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: the case for isradipine. Biochim. Biophys. Acta (BBA)-Mol. Basis Dis. 1812 (12), 1584–1590. Apolloni, S., Montilli, C., Finocchi, P., Amadio, S., 2009. Membrane compartments and purinergic signalling: p2X receptors in neurodegenerative and neuroinflammatory events. FEBS J. 276 (2), 354–364. Appelqvist, H., Wäster, P., Kågedal, K., Öllinger, K., 2013. The lysosome: from waste bag to potential therapeutic target. J. Mol. Cell Biol. 5 (4), 214–226. Araki, W., Yuasa, K., Takeda, S.I., Takeda, K., Shirotani, K., Takahashi, K., Tabira, T., 2001. Pro‐apoptotic effect of presenilin 2 (PS2) overexpression is associated with down‐regulation of Bcl-2 in cultured neurons. J. Neurochem. 79 (6), 1161–1168. Araque, A., Sanzgiri, R.P., Parpura, V., Haydon, P.G., 1998. Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. J. Neurosci. 18 (17), 6822–6829. Arispe, N., Rojas, E., Pollard, H.B., 1993. Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc. Natl. Acad. Sci. 90 (2), 567–571. Arking, R., Burde, V., Graves, K., Hari, R., Feldman, E., Zeevi, A., Soliman, S., Saraiya, A., Buck, S., Vettraino, J., Sathrasala, K., 2000. Forward and reverse selection for longevity in Drosophila is characterized by alteration of antioxidant gene expression and oxidative damage patterns. Exp. Gerontol. 35 (2), 167–185. Artal-Sanz, M., Tavernarakis, N., 2005. Proteolytic mechanisms in necrotic cell death and neurodegeneration. FEBS Lett. 579 (15), 3287–3296. Bacman, S.R., Bradley, W.G., Moraes, C.T., 2006. Mitochondrial involvement in amyotophic lateral sclerosis. Mol. Neurobiol. 33 (2), 113–131. Bading, H., Ginty, D.D., Greenberg, M.E., 1993. Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways. Science 260 (5105), 181–186. Bading, H., 2013. Nuclear calcium signalling in the regulation of brain function. Nat. Rev. Neurosci. 14 (9), 593–608. Bai, L., Hof, P.R., Standaert, D.G., Xing, Y., Nelson, S.E., Young, A.B., Magnusson, K.R., 2004. Changes in the expression of the NR2B subunit during aging in macaque monkeys. Neurobiol. Aging 25 (2), 201–208.

14

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al. 2008. Ischemia enhances activation by Ca2+ and redox modification of ryanodine receptor channels from rat brain cortex. J. Neurosci. 28 (38), 9463–9472. Burnstock, G., Dale, N., 2015. Purinergic signalling during development and aging. Purinergic Signal. 11 (3), 277–305. Calì, T., Ottolini, D., Negro, A., Brini, M., 2013. Enhanced parkin levels favor ER-mitochondria crosstalk and guarantee Ca 2+ transfer to sustain cell bioenergetics. Biochim. Biophys. Acta (BBA)-Mol. Basis Dis. 1832 (4), 495–508. Camandola, S., Mattson, M.P., 2017. Brain metabolism in health, aging, and neurodegeneration. The EMBO Journal pp. e201695810. Campbell, L.W., Hao, S.Y., Thibault, O., Blalock, E.M., Landfield, P.W., 1996. Aging changes in voltage-gated calcium currents in hippocampal CA1 neurons. J. Neurosci. 16 (19), 6286–6295. Cao, X., Cui, Z., Feng, R., Tang, Y.P., Qin, Z., Mei, B., Tsien, J.Z., 2007. Maintenance of superior learning and memory function in NR2B transgenic mice during aging. Eur. J. Neurosci. 25 (6), 1815–1822. Cavaliere, F., Florenzano, F., Amadio, S., Fusco, F.R., Viscomi, M.T., D'Ambrosi, N., Vacca, F., Sancesario, G., Bernardi, G., Molinari, M., Volonte, C., 2003. Up-regulation of P2 × 2, P2 × 4 receptor and ischemic cell death: prevention by P2 antagonists. Neuroscience 120 (1), 85–98. Cerbai, F., Lana, D., Nosi, D., Petkova-Kirova, P., Zecchi, S., Brothers, H.M., Wenk, G.L., Giovannini, M.G., 2012. The neuron-astrocyte-microglia triad in normal brain aging and in a model of neuroinflammation in the rat hippocampus. PLoS One 7 (9), e45250. Chakfe, Y., Seguin, R., Antel, J.P., Morissette, C., Malo, D., Henderson, D., Séguéla, P., 2002. ADP and AMP induce interleukin-1 (release from microglial cells through activation of ATP-primed P2 × 7 receptor channels. J. Neurosci. 22 (8), 3061–3069. Chakravarti, B., Chakravarti, D.N., 2006. Oxidative modification of proteins: age-related changes. Gerontology 53 (3), 128–139. Chakroborty, S., Briggs, C., Miller, M.B., Goussakov, I., Schneider, C., Kim, J., Wicks, J., Richardson, J.C., Conklin, V., Cameransi, B.G., Stutzmann, G.E., 2012. Stabilizing ER Ca 2+ channel function as an early preventative strategy for Alzheimer’s disease. PLoS One 7 (12), e52056. Chan, S.L., Mayne, M., Holden, C.P., Geiger, J.D., Mattson, M.P., 2000. Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J. Biol. Chem. 275 (24), 18195–18200. Chaturvedi, R.K., Beal, M.F., 2008. Mitochondrial approaches for neuroprotection. Ann. N. Y. Acad. Sci. 1147, 395–412. Chaudhari, N., Talwar, P., Parimisetty, A., Lefebvre d’Hellencourt, C., Ravanan, P., 2014. A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front. Cell. Neurosci. 213. Chen, Q.S., Wei, W.Z., Shimahara, T., Xie, C.W., 2002. Alzheimer amyloid (-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus. Neurobiol. Learn. Mem. 77 (3), 354–371. Cheung, K.H., Shineman, D., Müller, M., Cardenas, C., Mei, L., Yang, J., Tomita, T., Iwatsubo, T., Lee, V.M.Y., Foskett, J.K., 2008. Mechanism of Ca 2+ disruption in Alzheimer's disease by presenilin regulation of InsP 3 receptor channel gating. Neuron 58 (6), 871–883. Chohan, M.O., Iqbal, K., 2006. From tau to toxicity: emerging roles of NMDA receptor in Alzheimer's disease. J. Alzheimer's Dis. 10 (1), 81–87. Choi, Y.B., Chen, H.S.V., Lipton, S.A., 2001. Three pairs of cysteine residues mediate both redox and zn2+ modulation of the nmda receptor. J. Neurosci. 21 (2), 392–400. Choi, C.H., Schoenfeld, B.P., Bell, A.J., Hinchey, P., Kollaros, M., Gertner, M.J., Woo, N.H., Tranfaglia, M.R., Bear, M.F., Zukin, R.S., McDonald, T.V., 2011. Pharmacological reversal of synaptic plasticity deficits in the mouse model of fragile X syndrome by group II mGluR antagonist or lithium treatment. Brain Res. 1380, 106–119. Choi, D.W., 1992. Excitotoxic cell death. Dev. Neurobiol. 23 (9), 1261–1276. Chu, X.P., Xiong, Z.G., 2013. Acid-sensing ion channels in pathological conditions. Sodium Calcium Exchange: A Growing Spectrum of Pathophysiological Implications. Springer, US, pp. 419–431. Chung, H.J., Huang, Y.H., Lau, L.F., Huganir, R.L., 2004. Regulation of the NMDA receptor complex and trafficking by activity-dependent phosphorylation of the NR2B subunit PDZ ligand. J. Neurosci. 24 (45), 10248–10259. Cline, S.D., 2012. Mitochondrial DNA damage and its consequences for mitochondrial gene expression. Biochim. Biophys. Acta (BBA)-Gene Regul. Mech. 1819 (9), 979–991. Coddou, C., Yan, Z., Obsil, T., Huidobro-Toro, J.P., Stojilkovic, S.S., 2011. Activation and regulation of purinergic P2X receptor channels. Pharmacol. Rev. 63 (3), 641–683. Collingridge, G., 1987. The role of NMDA receptors in learning and memory. Nature 330 (6149), 604–605. Cook, N.L., Heuvel Cvd, Vink, R., 2009. Characterisation of TRPM channel mRNA levels in parkinson disease: In: the 12th international magnesium symposium. Magnes. Res. 22 (3), 188–189. Corral-Debrinski, M., Horton, T., Lott, M.T., Shoffner, J.M., Beal, M.F., Wallace, D.C., 1992. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat. Genet. 2 (4), 324–329. Corral-Debrinski, M., Horton, T., Lott, M.T., Shoffner, J.M., McKee, A.C., Beal, M.F., Graham, B.H., Wallace, D.C., 1994. Marked changes in mitochondrial DNA deletion levels in Alzheimer brains. Genomics 23 (2), 471–476. Cotman, C.W., Geddes, J.W., Bridges, R.J., Monaghan, D.T., 1989. N-methyl-D-aspartate receptors and Alzheimer's disease. Neurobiol. Aging 10 (5), 603–605. Csordás, G., Renken, C., Várnai, P., Walter, L., Weaver, D., Buttle, K.F., Balla, T., Mannella, C.A., Hajnóczky, G., 2006. Structural and functional features and significance of the physical linkage between ER and mitochondria. J. Cell Biol. 174 (7), 915–921. D'amelio, M., Cavallucci, V., Cecconi, F., 2010. Neuronal caspase-3 signaling: not only cell

death. Cell Death Differ. 17 (7), 1104–1114. Danysz, W., Parsons, C.G., 2012. Alzheimer's disease, β‐amyloid, glutamate, NMDA receptors and memantine–searching for the connections. Br. J. Pharmacol. 167 (2), 324–352. Daum, G., 1985. Lipids of mitochondria. Biochim. Biophys. Acta (BBA)-Rev. Biomembr. 822 (1), 1–42. De Felice, F.G., Velasco, P.T., Lambert, M.P., Viola, K., Fernandez, S.J., Ferreira, S.T., Klein, W.L., 2007. Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J. Biol. Chem. 282 (15), 11590–11601. Dean, J.B., Mulkey, D.K., Henderson, R.A., Potter, S.J., Putnam, R.W., 2004. Hyperoxia, reactive oxygen species, and hyperventilation: oxygen sensitivity of brain stem neurons. J. Appl. Physiol. 96 (2), 784–791. Deitmer, J.W., Verkhratsky, A.J., Lohr, C., 1998. Calcium signalling in glial cells. Cell Calcium 24 (5–6), 405–416. Delbono, O.S.V.A.L.D.O., Garcia, J., Appel, S.H., Stefani, E.N.R.I.C.O., 1991. IgG from amyotrophic lateral sclerosis affects tubular calcium channels of skeletal muscle. Am. J. Physiol. Cell Physiol. 260 (6), C1347–C1351. Delbono, O.S.V.A.L.D.O., Magnelli, V.A.L.E.R.I.A., Sawada, T.A.D.A.O., Smith, R.G., Appel, S.H., Stefani, E.N.R.I.C.O., 1993. Fab fragments from amyotrophic lateral sclerosis IgG affect calcium channels of skeletal muscle. Am. J. Physiol. Cell Physiol. 264 (3), C537–C543. Demuro, A., Parker, I., 2013. Cytotoxicity of intracellular aβ42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate. J. Neurosci. 33 (9), 3824–3833. Dent, M.A., Raisman, G., Lai, F.A., 1996. Expression of type 1 inositol 1, 4, 5-trisphosphate receptor during axogenesis and synaptic contact in the central and peripheral nervous system of developing rat. Development 122 (3), 1029–1039. Denton, R.M., 2009. Regulation of mitochondrial dehydrogenases by calcium ions. Biochim. Biophys. Acta (BBA)-Bioenergetics 1787 (11), 1309–1316. Dhaliwal, G.K., Grewal, R.P., 2000. Mitochondrial DNA deletion mutation levels are elevated in ALS brains. Neuroreport 11 (11), 2507–2509. Dieterich, D.C., Karpova, A., Mikhaylova, M., Zdobnova, I., König, I., Landwehr, M., Kreutz, M., Smalla, K.H., Richter, K., Landgraf, P., Reissner, C., 2008. Caldendrin–Jacob: a protein liaison that couples NMDA receptor signalling to the nucleus. PLoS Biol. 6 (2), e34. Disterhoft, J.F., Thompson, L.T., Moyer, J.R., Mogul, D.J., 1996. Calcium-dependent afterhyperpolarization and learning in young and aging hippocampus. Life Sci. 59 (5–6), 413–420. Dolmetsch, R.E., Pajvani, U., Fife, K., Spotts, J.M., Greenberg, M.E., 2001. Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 294 (5541), 333–339. Doonan, R., McElwee, J.J., Matthijssens, F., Walker, G.A., Houthoofd, K., Back, P., Matscheski, A., Vanfleteren, J.R., Gems, D., 2008. Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes. Dev. 22 (23), 3236–3241. Earnshaw, W.C., Martins, L.M., Kaufmann, S.H., 1999. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem 68 (1), 383–424. Eckles-Smith, K., Clayton, D., Bickford, P., Browning, M.D., 2000. Caloric restriction prevents age-related deficits in LTP and in NMDA receptor expression. Mol. Brain Res. 78 (1), 154–162. Ercal, N., Gurer-Orhan, H., Aykin-Burns, N., 2001. Toxic metals and oxidative stress part I: mechanisms involved in metal-induced oxidative damage. Curr. Top. Med. Chem. 1 (6), 529–539. Ermak, G., Davies, K.J., 2002. Calcium and oxidative stress: from cell signaling to cell death. Mol. Immunol. 38 (10), 713–721. Erulkar, S.D., Fine, A., 1979. Calcium in the nervous system. Rev. Neurosci. 4, 179–232. Ethell, D.W., Buhler, L.A., 2003. Fas ligand-mediated apoptosis in degenerative disorders of the brain. J. Clin. Immunol. 23 (5), 363–370. Evans, M.D., Dizdaroglu, M., Cooke, M.S., 2004. Oxidative DNA damage and disease: induction, repair and significance. Mutat. Res. Rev. Mutat. Res. 567 (1), 1–61. Fabris, N., 1991. Neuroendocrine-immune interactions: a theoretical approach to aging. Arch. Gerontol. Geriatr. 12 (2–3), 219–230. Fan, M.M., Fernandes, H.B., Zhang, L.Y., Hayden, M.R., Raymond, L.A., 2007. Altered NMDA receptor trafficking in a yeast artificial chromosome transgenic mouse model of Huntington's disease. J. Neurosci. 27 (14), 3768–3779. Feissner, R.F., Skalska, J., Gaum, W.E., Sheu, S.S., 2009. Crosstalk signaling between mitochondrial Ca2+ and ROS. ABBV Front Biosci 1197. Fern, R., Möller, T., 2000. Rapid ischemic cell death in immature oligodendrocytes: a fatal glutamate release feedback loop. J. Neurosci. 20 (1), 34–42. Fields, R.D., Stevens, B., 2000. ATP: an extracellular signaling molecule between neurons and glia. Trends Neurosci. 23 (12), 625–633. Floyd, R.A., Hensley, K., 2002. Oxidative stress in brain aging: implications for therapeutics of neurodegenerative diseases. Neurobiol. Aging 23 (5), 795–807. Franceschi, C., Bonafè, M., Valensin, S., Olivieri, F., De Luca, M., Ottaviani, E., De Benedictis, G., 2000. Inflamm‐aging: an evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908 (1), 244–254. Franceschi, C., 1989. Cell proliferation, cell death and aging. Aging Clin. Exp. Res. 1 (1), 3–15. Frieden, M., James, D., Castelbou, C., Danckaert, A., Martinou, J.C., Demaurex, N., 2004. Ca2+ homeostasis during mitochondrial fragmentation and perinuclear clustering induced by hFis1. J. Biol. Chem. 279 (21), 22704–22714. Fujino, Y., Ozaki, K., Yamamasu, S., Ito, F., Matsuoka, I., Hayashi, E., Nakamura, H., Ogita, S., Sato, E., Inoue, M., 1996. Ovary and ovulation: DNA fragmentation of oocytes in aged mice. Hum. Reprod. 11 (7), 1480–1483.

15

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

undefined terminology explains misunderstanding both. PLoS Genet. 3 (12), e220. Help Age India, 2015. State of Elderly in India 2014. New Delhi : Help Age India. 182p. Report No.: ISBN:9789384439354. Henchcliffe, C., Beal, M.F., 2008. Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat. Clin. Pract. Neurol. 4 (11), 600–609. Hensley, K., Carney, J.M., Mattson, M.P., Aksenova, M., Harris, M., Wu, J.F., Floyd, R.A., Butterfield, D.A., 1994. A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc. Natl. Acad. Sci. 91 (8), 3270–3274. Heron, M.P., Hoyert, D.L., Murphy, S.L., Xu, J.Q., Kochanek, K.D., TejadaVera, B., 2009. 14. Deaths: Final Data for 2006. National Vital Statistics Reports 57 U.S. Department of Health and Human Services . National Center for Health Statistics, Hyattsville, MD. Hervias, I., Beal, M.F., Manfredi, G., 2006. Mitochondrial dysfunction and amyotrophic lateral sclerosis. Muscle Nerve 33 (5), 598–608. Hetman, M., Kharebava, G., 2006. Survival signaling pathways activated by NMDA receptors. Curr. Top. Med. Chem. 6 (8), 787–799. Hidalgo, C., Bull, R., Behrens, M.I., Donoso, P., 2004. Redox regulation of RyR-mediated Ca2+ release in muscle and neurons. Biol. Res. 37 (4), 539–552. Hinds, J.W., McNelly, N.A., 1978. Dispersion of cisternae of rough endoplasmic reticulum in aging CNS neurons: a strictly linear trend. Am. J. Anat. 152 (3), 433–439. Hoey, S.E., Williams, R.J., Perkinton, M.S., 2009. Synaptic NMDA receptor activation stimulates α-secretase amyloid precursor protein processing and inhibits amyloid-β production. J. Neurosci. 29 (14), 4442–4460. Hollmann, M., Hartley, M., Heinemann, S., 1991. Ca (2plus) permeability of KA-AMPAGated glutamate receptor channels depends on subunit composition. Science 252 (5007), 851. Hopp, S.C., D’Angelo, H.M., Royer, S.E., Kaercher, R.M., Adzovic, L., Wenk, G.L., 2014. Differential rescue of spatial memory deficits in aged rats by L-type voltage-dependent calcium channel and ryanodine receptor antagonism. Neuroscience 280, 10–18. Horton, T.M., Graham, B.H., Corral-Debrinski, M., Shoffner, J.M., Kaufman, A.E., Beal, M.F., Wallace, D.C., 1995. Marked increase in mitochondrial DNA deletion levels in the cerebral cortex of Huntington's disease patients. Neurology 45 (10), 1879–1883. Hsieh, H., Boehm, J., Sato, C., Iwatsubo, T., Tomita, T., Sisodia, S., Malinow, R., 2006. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 52 (5), 831–843. Hu, N.W., Klyubin, I., Anwyl, R., Rowan, M.J., 2009. GluN2B subunit-containing NMDA receptor antagonists prevent Aβ-mediated synaptic plasticity disruption in vivo. Proc. Natl. Acad. Sci. 106 (48), 20504–20509. Huddleston, A.T., Tang, W., Takeshima, H., Hamilton, S.L., Klann, E., 2008. Superoxideinduced potentiation in the hippocampus requires activation of ryanodine receptor type 3 and ERK. J. Neurophysiol. 99 (3), 1565–1571. Hugon, J., Hugon, F., Esclaire, F., Lesort, M., Diop, A.G., 1996. The presence of calbindin in rat cortical neurons protects in vitro from oxydative stress. Brain Res. 707 (2), 288–292. Iacopino, A.M., Christakos, S., 1990. Specific reduction of calcium-binding protein (28kilodalton calbindin-D) gene expression in aging and neurodegenerative diseases. Proc. Natl. Acad. Sci. 87 (11), 4078–4082. Ilijic, E., Guzman, J.N., Surmeier, D.J., 2011. The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson's disease. Neurobiol. Dis. 43 (2), 364–371. Ingram, D.K., Joseph, J.A., Spangler, E.L., Roberts, D., Hengemihle, J., Fanelli, R.J., 1994. Chronic nimodipine treatment in aged rats: analysis of motor and cognitive effects and muscarinic-induced striatal dopamine release. Neurobiol. Aging 15 (1), 55–61. Ito, E., Oka, K., Etcheberrigaray, R., Nelson, T.J., McPhie, D.L., Tofel-Grehl, B., Gibson, G.E., Alkon, D.L., 1994. Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease. Proc. Natl. Acad. Sci. 91 (2), 534–538. Jaiswal, M.K., 2014. Selective vulnerability of motor neuron and perturbed mitochondrial calcium homeostasis in amyotrophic lateral sclerosis: implications for motor neurons specific calcium dysregulation. Mol. Cell. Ther. 2 (1), 26. Jiang, D., Zhao, L., Clish, C.B., Clapham, D.E., 2013. Letm1, the mitochondrial Ca2+/H+ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf–Hirschhorn syndrome. Proc. Natl. Acad. Sci. 110 (24), E2249–E2254. Jin, J., Wu, L.J., Jun, J., Cheng, X., Xu, H., Andrews, N.C., Clapham, D.E., 2012. The channel kinase TRPM7, is required for early embryonic development. Proc. Natl. Acad. Sci. 109 (5), E225–E233. Kahns, S., Lykkebo, S., Jakobsen, L.D., Nielsen, M.S., Jensen, P.H., 2002. Caspase-mediated parkin cleavage in apoptotic cell death. J. Biol. Chem. 277 (18), 15303–15308. Kaltenbach, L.S., Romero, E., Becklin, R.R., Chettier, R., Bell, R., Phansalkar, A., Strand, A., Torcassi, C., Savage, J., Hurlburt, A., Cha, G.H., 2007. Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genet. 3 (5), e82. Kamat, P.K., Kalani, A., Rai, S., Swarnkar, S., Tota, S., Nath, C., Tyagi, N., 2016. Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease: understanding the Therapeutics strategies. Mol. Neurobiol. 53 (1), 648–661. Kanungo, M.S., 1975. A model for aging. J. Theor. Biol. 53, 253–261. Karpova, A., Mikhaylova, M., Bera, S., Bär, J., Reddy, P.P., Behnisch, T., Rankovic, V., Spilker, C., Bethge, P., Sahin, J., Kaushik, R., 2013. Encoding and transducing the synaptic or extrasynaptic origin of NMDA receptor signals to the nucleus. Cell 152 (5), 1119–1133. Kater, S.B., Mattson, M.P., Guthrie, P.B., 1989. Calcium‐Induced neuronal degeneration: a normal growth cone regulating signal gone awry (?). Ann. N. Y. Acad. Sci. 568 (1), 252–261. Kaufman, R.J., Malhotra, J.D., 2014. Calcium trafficking integrates endoplasmic reticulum function with mitochondrial bioenergetics. Biochim. et Biophys. Acta (BBA)Mol. Cell Res. 1843 (10), 2233–2239. Kawahara, M., Kuroda, Y., 2001. Intracellular calcium changes in neuronal cells induced

Gómez‐Gonzalo, M., Martin‐Fernandez, M., Martínez‐Murillo, R., Mederos, S., Hernández‐Vivanco, A., Jamison, S., Fernandez, A.P., Serrano, J., Calero, P., Futch, H.S., Corpas, R., 2017. Neuron–astrocyte signaling is preserved in the aging brain. Glia 65 (4), 569–580. Görlach, A., Klappa, P., Kietzmann, D.T., 2006. The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxidants & redox signaling 8 (9–10), 1391–1418. Gafni, J., Hermel, E., Young, J.E., Wellington, C.L., Hayden, M.R., Ellerby, L.M., 2004. Inhibition of calpain cleavage of huntingtin reduces toxicity accumulation of calpain/ caspase fragments in the nucleus. J. Biol. Chem. 279 (19), 20211–20220. Gallo, V., Patneau, D.K., Mayer, M.L., Vaccarino, F.M., 1994. Excitatory amino acid receptors in glial progenitor cells: molecular and functional properties. Glia 11 (2), 94–101. Gambetti, P., Erulkar, S.E., Somlyo, A.P., Gonatas, N.K., 1975. Calcium-containing structures in vertebrate glial cells: ultrastructural and microprobe analysis. J. Cell Biol. 64 (2), 322–330. Gandhi, S., Wood-Kaczmar, A., Yao, Z., Plun-Favreau, H., Deas, E., Klupsch, K., Downward, J., Latchman, D.S., Tabrizi, S.J., Wood, N.W., Duchen, M.R., 2009. PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calciuminduced cell death. Mol. Cell 33 (5), 627–638. Gant, J.C., Sama, M.M., Landfield, P.W., Thibault, O., 2006. Early and simultaneous emergence of multiple hippocampal biomarkers of aging is mediated by Ca2+-induced Ca2+ release. J. Neurosci. 26 (13), 3482–3490. Garber, K., 2008. The elusive ALS genes. Science 319 (5859) 20–20. Gees, M., Colsoul, B., Nilius, B., 2010. The role of transient receptor potential cation channels in Ca2+ signaling. Cold Spring Harbor Perspect. Biol. 2 (10), a003962. Gemma, C., Vila, J., Bachstetter, A., Bickford, P.C., 2007. Oxidative Stress and the Aging Brain: from Theory to Prevention. Gerendasy, D., 1999. Homeostatic tuning of Ca2+ signal transduction by members of the calpacitin protein family. J. Neurosci. Res. 58 (1), 107–119. Gleichmann, M., Mattson, M.P., 2011. Neuronal calcium homeostasis and dysregulation. Antioxid. Redox Signal. 14 (7), 1261–1273. Golovina, V.A., 2005. Visualization of localized store‐operated calcium entry in mouse astrocytes: close proximity to the endoplasmic reticulum. J. Physiol. 564 (3), 737–749. Gore, A.C., Oung, T., Woller, M.J., 2002. Age‐Related changes in hypothalamic gonadotropin‐releasing hormone and N‐Methyl‐d‐Aspartate receptor gene expression, and their regulation by oestrogen, in the female rat. J. Neuroendocrinol. 14 (4), 300–309. Grabert, K., Michoel, T., Karavolos, M.H., Clohisey, S., Baillie, J.K., Stevens, M.P., Freeman, T.C., Summers, K.M., McColl, B.W., 2016. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19 (3), 504–516. Green, D.R., Kroemer, G., 2004. The pathophysiology of mitochondrial cell death. Science 305 (5684), 626–629. Guo, Q., Sopher, B.L., Furukawa, K., Pham, D.G., Robinson, N., Martin, G.M., Mattson, M.P., 1997. Alzheimer’s presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid (-peptide: involvement of calcium and oxyradicals. J. Neurosci. 17 (11), 4212–4222. Gusella, J.F., MacDonald, M.E., 2000. Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nat. Rev. Neurosci. 1 (2), 109–115. Hüser, J., Blatter, L.A., 1999. Fluctuations in mitochondrial membrane potential caused by repetitive gating of the permeability transition pore. Biochem. J. 343 (2), 311–317. Hagen, T.M., Yowe, D.L., Bartholomew, J.C., Wehr, C.M., Do, K.L., Park, J.Y., Ames, B.N., 1997. Mitochondrial decay in hepatocytes from old rats: membrane potential declines, heterogeneity and oxidants increase. Proc. Natl. Acad. Sci. 94 (7), 3064–3069. Hagiwara, S.U.S.U.M.U., Byerly, L., 1981. Calcium channel. Annu. Rev. Neurosci. 4 (1), 69–125. Haldane, J.B.S., 1941. New paths in genetics. New paths in Genetics. Hallett, P.J., Standaert, D.G., 2004. Rationale for and use of NMDA receptor antagonists in Parkinson's disease. Pharmacol. Ther. 102 (2), 155–174. Hardingham, G.E., Bading, H., 2010. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat. Rev. Neurosci. 11 (10), 682–696. Harley, C.B., Vaziri, H., Counter, C.M., Allsopp, R.C., 1992. The telomere hypothesis of cellular aging. Exp. Gerontol. 27 (4), 375–382. Harman, D., 1956. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11 (3), 298–300. Harman, D., 1965. The free radical theory of aging: effect of age on serum copper levels. J. Gerontol. 20 (2), 151–153. Harman, D., 1972. The biologic clock: the mitochondria? J. Am. Geriatr. Soc. 20 (4), 145–147. Hartmann, A., Hunot, S., Michel, P.P., Muriel, M.P., Vyas, S., Faucheux, B.A., MouattPrigent, A., Turmel, H., Srinivasan, A., Ruberg, M., Evan, G.I., 2000. Caspase-3: a vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease. Proc. Natl. Acad. Sci. 97 (6), 2875–2880. Haughey, N.J., Mattson, M.P., 2002. Calcium dysregulation and neuronal apoptosis by the HIV-1 proteins Tat and gp120. J. Acquired Immune Deficiency Syndromes (1999) 31, S55–61. Haughey, N.J., Holden, C.P., Nath, A., Geiger, J.D., 1999. Involvement of inositol 1, 4, 5‐trisphosphate‐regulated stores of intracellular calcium in calcium dysregulation and neuron cell death caused by HIV‐1 protein tat. J. Neurochem. 73 (4), 1363–1374. Hayashi, Y., Ishibashi, H., Hashimoto, K., Nakanishi, H., 2006. Potentiation of the NMDA receptor‐mediated responses through the activation of the glycine site by microglia secreting soluble factors. Glia 53 (6), 660–668. Hayflick, L., 2007. Entropy explains aging, genetic determinism explains longevity, and

16

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

by Alzheimer's ß-amyloid protein are blocked by estradiol and cholesterol. Cell. Mol. Neurobiol. 21 (1), 1–13. Kawasaki, H., Morooka, T., Shimohama, S., Kimura, J., Hirano, T., Gotoh, Y., Nishida, E., 1997. Activation and involvement of p38 mitogen-activated protein kinase in glutamate-induced apoptosis in rat cerebellar granule cells. J. Biol. Chem. 272 (30), 18518–18521. Keller, J.N., Mark, R.J., Bruce, A.J., Blanc, E., Rothstein, J.D., Uchida, K., Waeg, G., Mattson, M.P., 1997. 4-Hydroxynonenal, an aldehydic product of membrane lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes. Neuroscience 80 (3), 685–696. Kelly, B.L., Ferreira, A., 2006. β-amyloid-induced dynamin 1 degradation is mediated by N-methyl-D-aspartate receptors in hippocampal neurons. J. Biol. Chem. 281 (38), 28079–28089. Kerr, J.F., Wyllie, A.H., Currie, A.R., 1972. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26 (4), p.239. Kerr, D.S., Campbell, L.W., Thibault, O., Landfield, P.W., 1992. Hippocampal glucocorticoid receptor activation enhances voltage-dependent Ca2+ conductances: relevance to brain aging. Proc. Natl. Acad. Sci. 89 (18), 8527–8531. Khachaturian, Z.S., Cotman, C.W., Pettegrew, J.W., 1989b. Introduction and overview on calcium membranes, aging, and Alzheimer’s disease. Ann. N. Y. Acad. Sci. 568, 1–4. Khachaturian, Z.S., 1986. Aluminum toxicity among other views on the etiology of Alzheimer disease. Neurobiol. Aging 7 (6), 537–539. Khachaturian, Z.S., 1989a. The role of calcium regulation in brain aging: reexamination of a hypothesis. Aging Clin. Exp. Res. 1 (1), 17–34. Khachaturian, Z.S., 1994. Calcium hypothesis of Alzheimer's disease and brain aging. Ann. N. Y. Acad. Sci. 747 (1), 1–11. Khodakhah, K., Ogden, D., 1993. Functional heterogeneity of calcium release by inositol trisphosphate in single Purkinje neurones, cultured cerebellar astrocytes, and peripheral tissues. Proc. Natl. Acad. Sci. 90 (11), 4976–4980. Kikuchi, H., Almer, G., Yamashita, S., Guégan, C., Nagai, M., Xu, Z., Sosunov, A.A., McKhann, G.M., Przedborski, S., 2006. Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. Proc. Natl. Acad. Sci. 103 (15), 6025–6030. Kim, B., Matsuoka, S., 2008. Cytoplasmic Na + ‐dependent modulation of mitochondrial Ca2+ via electrogenic mitochondrial Na + –Ca2+ exchange. J. Physiol. 586 (6), 1683–1697. Kim, I., Xu, W., Reed, J.C., 2008. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 7 (12), 1013–1030. Kirischuk, S., Verkhratsky, A., 1996. Calcium homeostasis in aged neurones. Life Sci. 59 (5-6), 451–459. Kirischuk, S., Scherer, J., Möller, T., Verkhratsky, A., Kettenmann, H., 1995. Subcellular heterogeneity of voltage‐gated Ca2+ channels in cells of the oligodendrocyte lineage. Glia 13 (1), 1–12. Kirkwood, T., Kirkwood, T.B., 2003. The most pressing problem of our age. BMJ: Br. Med. J. 1297–1299. Klaunig, J.E., Wang, Z., Pu, X., Zhou, S., 2011. Oxidative stress and oxidative damage in chemical carcinogenesis. Toxicol. Appl. Pharmacol. 254 (2), 86–99. Kostyuk, P., Verkhratsky, A., 1994. Calcium stores in neurons and glia. Neuroscience 63 (2), 381–404. Kourie, J.I., Henry, C.L., 2002. Ion channel formation and membrane‐linked pathologies of misfolded hydrophobic proteins: the role of dangerous unchaperoned molecules. Clin. Exp. Pharmacol. Physiol. 29 (9), 741–753. Kovacic, P., Osuna, J., 2000. Mechanisms of anti-cancer agents emphasis on oxidative stress and electron transfer. Curr. Pharm. Des. 6 (3), 277–309. Kraytsberg, Y., Kudryavtseva, E., McKee, A.C., Geula, C., Kowall, N.W., Khrapko, K., 2006. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat. Genet. 38 (5), 518–520. Krishnan, K.J., Reeve, A.K., Samuels, D.C., Chinnery, P.F., Blackwood, J.K., Taylor, R.W., Wanrooij, S., Spelbrink, J.N., Lightowlers, R.N., Turnbull, D.M., 2008. What causes mitochondrial DNA deletions in human cells? Nat. Genet. 40 (3), 275–279. Kruman, I.I., Nath, A., Mattson, M.P., 1998. HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp. Neurol. 154 (2), 276–288. Kuchibhotla, K.V., Goldman, S.T., Lattarulo, C.R., Wu, H.Y., Hyman, B.T., Bacskai, B.J., 2008. Aβ plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 59 (2), 214–225. Kuhn, A., Goldstein, D.R., Hodges, A., Strand, A.D., Sengstag, T., Kooperberg, C., Becanovic, K., Pouladi, M.A., Sathasivam, K., Cha, J.H.J., Hannan, A.J., 2007. Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage. Hum. Mol. Genet. 16 (15), 1845–1861. Kujoth, G.C., Hiona, A., Pugh, T.D., Someya, S., Panzer, K., Wohlgemuth, S.E., Hofer, T., Seo, A.Y., Sullivan, R., Jobling, W.A., Morrow, J.D., 2005. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309 (5733), 481–484. Kumar, A., Bodhinathan, K., Foster, T.C., 2009. Susceptibility to calcium dysregulation during brain aging. Front. Aging Neurosci. 1, 2. Kwong, L.K., Sohal, R.S., 2000. Age-related changes in activities of mitochondrial electron transport complexes in various tissues of the mouse. Arch. Biochem. Biophys. 373 (1), 16–22. López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M., Kroemer, G., 2013. The hallmarks of aging. Cell 153 (6), 1194–1217. Lalo, U., Palygin, O., North, R.A., Verkhratsky, A., Pankratov, Y., 2011. Age‐dependent remodelling of ionotropic signalling in cortical astroglia. Aging cell 10 (3), 392–402. Lamont, M.G., Weber, J.T., 2012. The role of calcium in synaptic plasticity and motor

learning in the cerebellar cortex. Neurosci. Biobehav. Rev. 36 (4), 1153–1162. Landfield, P.W., Eldridge, J.C., 1994. The glucocorticoid hypothesis of age‐related hippocampal neurodegeneration: role of dysregulated intraneuronal calcium. Ann. N. Y. Acad. Sci. 746 (1), 308–321. Lee, G., Pollard, H.B., Arispe, N., 2002. Annexin 5 and apolipoprotein E2 protect against Alzheimer’s amyloid-β-peptide cytotoxicity by competitive inhibition at a common phosphatidylserine interaction site. Peptides 23 (7), 1249–1263. Lee, H.K., Min, S.S., Gallagher, M., Kirkwood, A., 2005. NMDA receptor-independent long-term depression correlates with successful aging in rats. Nat. Neurosci. 8 (12), p.1657. Lehohla, M., Kellaway, L., Russell, V.A., 2008. Effect of aging on Ca2+ uptake via NMDA receptors into barrel cortex slices of spontaneously hypertensive rats. Metab. Brain Dis. 23 (1), 1–8. Lei, S.Z., Zhang, D., Abele, A.E., Lipton, S.A., 1992. Blockade of NMDA receptor-mediated mobilization of intracellular Ca 2+ prevents neurotoxicity. Brain Res. 598 (1), 196–202. Leissring, M.A., Akbari, Y., Fanger, C.M., Cahalan, M.D., Mattson, M.P., LaFerla, F.M., 2000. Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J. Cell Biol. 149 (4), 793–798. Levine, B., Yuan, J., 2005. Autophagy in cell death: an innocent convict? J. Clin. Invest. 115 (10), 2679–2688. Levy, A., Kong, R.M., Stillman, M.J., Shukitt-Hale, B., Kadar, T., Rauch, T.M., Lieberman, H.R., 1991. Nimodipine improves spatial working memory and elevates hippocampal acetylcholine in young rats. Pharmacol. Biochem. Behav. 39 (3), 781–786. Li, S., Jin, M., Koeglsperger, T., Shepardson, N.E., Shankar, G.M., Selkoe, D.J., 2011. Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J. Neurosci. 31 (18), 6627–6638. Lin, M.T., Beal, M.F., 2006. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443 (7113), 787–795. Lin, M.T., Simon, D.K., Ahn, C.H., Kim, L.M., Beal, M.F., 2002. High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer’s disease brain. Hum. Mol. Genet. 11 (2), 133–145. Lin, Y., Jover-Mengual, T., Wong, J., Bennett, M.V., Zukin, R.S., 2006. PSD-95 and PKC converge in regulating NMDA receptor trafficking and gating. Proc. Natl. Acad. Sci. 103 (52), 19902–19907. Lisman, J.E., Fellous, J.M., Wang, X.J., 1998. A role for NMDA-receptor channels in working memory. Nat. Neurosci. 1 (4), 273–275. Liu, H.N., Almazan, G., 1995. Glutamate induces c‐fos proto‐oncogene expression and inhibits proliferation in oligodendrocyte progenitors: receptor characterization. Eur. J. Neurosci. 7 (12), 2355–2363. Liu, J., Mori, A., 1999. Stress, aging, and brain oxidative damage. Neurochem. Res. 24 (11), 1479–1497. Liu, J., Lillo, C., Jonsson, P.A., Velde, C.V., Ward, C.M., Miller, T.M., Subramaniam, J.R., Rothstein, J.D., Marklund, S., Andersen, P.M., Brännström, T., 2004a. Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron 43 (1), 5–17. Liu, X.B., Murray, K.D., Jones, E.G., 2004b. Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development. J. Neurosci. 24 (40), 8885–8895. Liu, P., Smith, P.F., Darlington, C.L., 2008. Glutamate receptor subunits expression in memory‐associated brain structures: regional variations and effects of aging. Synapse 62 (11), 834–841. Liu, J., Supnet, C., Sun, S., Zhang, H., Good, L., Popugaeva, E., Bezprozvanny, I., 2014. The role of ryanodine receptor type 3 in a mouse model of Alzheimer disease. Channels 8 (3), 230–242. Lopez‐Meraz, M.L., Niquet, J., Wasterlain, C.G., 2010. Distinct caspase pathways mediate necrosis and apoptosis in subpopulations of hippocampal neurons after status epilepticus. Epilepsia 51 (s3), 56–60. Louneva, N., Cohen, J.W., Han, L.Y., Talbot, K., Wilson, R.S., Bennett, D.A., Trojanowski, J.Q., Arnold, S.E., 2008. Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer's disease. Am. J. Pathol. 173 (5), 1488–1495. Lu, Y.M., Jia, Z., Janus, C., Henderson, J.T., Gerlai, R., Wojtowicz, J.M., Roder, J.C., 1997. Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J. Neurosci. 17 (13), 5196–5205. Lu, T., Pan, Y., Kao, S.Y., Li, C., Kohane, I., Chan, J., Yankner, B.A., 2004. Gene regulation and DNA damage in the aging human brain. Nature 429 (6994), 883–891. Lynch, G., Bi, X., 2003. Lysosomes and brain aging in mammals. Neurochem. Res. 28 (11), 1725–1734. Magnusson, K.R., Bai, L., Zhao, X., 2005. The effects of aging on different C-terminal splice forms of the (1 (NR1) subunit of the N-methyl-d-aspartate receptor in mice. Mol. Brain Res. 135 (1), 141–149. Magnusson, K.R., 1998. The aging of the NMDA receptor complex. Front. Biosci. 3, e70–e80. Magnusson, K.R., 2000. Declines in mRNA expression of different subunits may account for differential effects of aging on agonist and antagonist binding to the NMDA receptor. J. Neurosci. 20 (5), 1666–1674. Magnusson, K.R., 2001. Influence of diet restriction on NMDA receptor subunits and learning during aging. Neurobiol. Aging 22 (4), 613–627. Magnusson, K.R., 2012. Aging of the NMDA receptor: from a mouse’s point of view. Future Neurol. 7 (5), 627–637. Magrané, J., Manfredi, G., 2009. Mitochondrial function, morphology, and axonal transport in amyotrophic lateral sclerosis. Antioxid. Redox Signal. 11 (7), 1615–1626. Malenka, R.C., Nicoll, R.A., 1999. Long-term potentiation–a decade of progress? Science 285 (5435), 1870–1874.

17

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

2009. Enhanced susceptibility to MPTP neurotoxicity in magnesium-deficient C57BL/ 6N mice. Neurosci. Res. 63 (1), 72–75. Murray, T.K., Messenger, M.J., Ward, M.A., Woodhouse, S., Osborne, D.J., Duty, S., O'Neill, M.J., 2002. Evaluation of the mGluR2/3 agonist LY379268 in rodent models of Parkinson's disease. Pharmacol. Biochem. Behav. 73 (2), 455–466. Nadler, M.J., Hermosura, M.C., Inabe, K., Perraud, A.L., Zhu, Q., Stokes, A.J., Kurosaki, T., Kinet, J.P., Penner, R., Scharenberg, A.M., Fleig, A., 2001. LTRPC7 is a Mg· ATPregulated divalent cation channel required for cell viability. Nature 411 (6837), 590–595. Naidoo, N., Ferber, M., Master, M., Zhu, Y., Pack, A.I., 2008. Aging impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling. J. Neurosci. 28 (26), 6539–6548. Nakagawa, T., Okano, H., Furuichi, T., Aruga, J., Mikoshiba, K., 1991. The subtypes of the mouse inositol 1, 4, 5-trisphosphate receptor are expressed in a tissue-specific and developmentally specific manner. Proc. Natl. Acad. Sci. 88 (14), 6244–6248. Nakanishi, H., Amano, T., Sastradipura, D.F., Yoshimine, Y., Tsukuba, T., Tanabe, K., Hirotsu, I., Ohono, T., Yamamoto, K., 1997. Increased expression of cathepsins E and D in neurons of the aged rat brain and their colocalization with lipofuscin and carboxy‐terminal fragments of Alzheimer amyloid precursor protein. J. Neurochem. 68 (2), 739–749. Nath, A., 2002. Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J. Infect. Dis. 186 (Suppl. 2), S193–S198. Nazıroğlu, M., Şenol, N., Ghazizadeh, V., Yürüker, V., 2014. Neuroprotection induced by N-acetylcysteine and selenium against traumatic brain injury-induced apoptosis and calcium entry in hippocampus of rat. Cell. Mol. Neurobiol. 34 (6), 895–903. Nazıroğlu, M., 2012. Molecular role of catalase on oxidative stress-induced Ca2+ signaling and TRP cation channel activation in nervous system. J. Recept. Signal Transduction 32 (3), 134–141. Nedergaard, M., 1994. Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science-AAAS-Weekly Paper Edition-including Guide to Scientific Information, vol. 263. pp. 1768–1770. Nelson, O., Tu, H., Lei, T., Bentahir, M., De Strooper, B., Bezprozvanny, I., 2007. Familial Alzheimer disease–linked mutations specifically disrupt Ca 2+ leak function of presenilin 1. J. Clin. Invest. 117 (5), 1230–1239. Newman, E.A., 1985. Voltage-dependent calcium and potassium channels in retinal glial cells. Nature 317 (6040), 809. Neyman, S., Manahan‐Vaughan, D., 2008. Metabotropic glutamate receptor 1 (mGluR1) and 5 (mGluR5) regulate late phases of LTP and LTD in the hippocampal CA1 region in vitro. Eur. J. Neurosci. 27 (6), 1345–1352. Niccoli, T., Partridge, L., 2012. Ageing as a risk factor for disease. Curr. Biol. 22 (17), R741–R752. Nicholls, D.G., 2005. Mitochondria and calcium signaling. Cell Calcium 38 (3), 311–317. Nikoletopoulou, V., Markaki, M., Palikaras, K., Tavernarakis, N., 2013. Crosstalk between apoptosis, necrosis and autophagy. Bioch. Biophys. Acta (BBA)-Mol. Cell Res. 1833 (12), 3448–3459. Nimmrich, V., Grimm, C., Draguhn, A., Barghorn, S., Lehmann, A., Schoemaker, H., Hillen, H., Gross, G., Ebert, U., Bruehl, C., 2008. Amyloid (oligomers (A(1–42 globulomer) suppress spontaneous synaptic activity by inhibition of P/Q-type calcium currents. J. Neurosci. 28 (4), 788–797. Niquet, J., Seo, D.W., Wasterlain, C.G., 2006. Mitochondrial pathways of neuronal necrosis. Nixon, R.A., 2013. The role of autophagy in neurodegenerative disease. Nat. Med. 19 (8), 983–997. Norris, C.M., Halpain, S., Foster, T.C., 1998. Alterations in the balance of protein kinase/ phosphatase activities parallel reduced synaptic strength during aging. J. Neurophysiol. 80 (3), 1567–1570. Nunomura, A., Moreira, P.I., Lee, H.G., Zhu, X., Castellani, R.J., Smith, M.A., Perry, G., 2007. Neuronal death and survival under oxidative stress in Alzheimer and Parkinson diseases. CNS Neurol. Disord. rug Targets (Formerly Curr. Drug Targets CNS Neurol. Disord.) 6 (6), 411–423. Övey, I.S., Naziroğlu, M., 2015. Homocysteine and cytosolic GSH depletion induce apoptosis and oxidative toxicity through cytosolic calcium overload in the hippocampus of aged mice: involvement of TRPM2 and TRPV1 channels. Neuroscience 284, 225–233. Orrenius, S., Zhivotovsky, B., Nicotera, P., 2003. Regulation of cell death: the calcium?apoptosis link. Nat. Rev. Mol. Cell Biol. 4 (7), 552–565. Oyanagi, K., Kawakami, E., Kikuchi‐Horie, K., Ohara, K., Ogata, K., Takahama, S., Wada, M., Kihira, T., Yasui, M., 2006. Magnesium deficiency over generations in rats with special references to the pathogenesis of the parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam. Neuropathology 26 (2), 115–128. Pérez, V.I., Van Remmen, H., Bokov, A., Epstein, C.J., Vijg, J., Richardson, A., 2009. The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging cell 8 (1), 73–75. Palmer, D.B., 2013. The effect of age on thymic function. Front. Immunol. 4. Park, C.B., Larsson, N.G., 2011. Mitochondrial DNA mutations in disease and aging. J. Cell Biol. 193 (5), 809–818. Pasinelli, P., Brown, R.H., 2006. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat. Rev. Neurosci. 7 (9), 710–723. Patneau, D.K., Wright, P.W., Winters, C., Mayer, M.L., Gallo, V., 1994. Glial cells of the oligodendrocyte lineage express both kainate-and AMPA-preferring subtypes of glutamate receptor. Neuron 12 (2), 357–371. Pende, M., Holtzclaw, L.A., Curtis, J.L., Russell, J.T., Gallo, V., 1994. Glutamate regulates intracellular calcium and gene expression in oligodendrocyte progenitors through the activation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Proc. Natl. Acad. Sci. 91 (8), 3215–3219. Pertusa, M., Garcia‐Matas, S., Rodriguez‐Farre, E., Sanfeliu, C., Cristofol, R., 2007.

Malkus, K.A., Tsika, E., Ischiropoulos, H., 2009. Oxidative modifications, mitochondrial dysfunction, and impaired protein degradation in Parkinson's disease: how neurons are lost in the Bermuda triangle. Mol. Neurodegener. 4 (1), 24. Manahan-Vaughan, D., Braunewell, K.H., 2005. The metabotropic glutamate receptor, mGluR5, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity. Cereb. Cortex 15 (11), 1703–1713. Manahan-Vaughan, D., 1997. Group 1 and 2 metabotropic glutamate receptors play differential roles in hippocampal long-term depression and long-term potentiation in freely moving rats. J. Neurosci. 17 (9), 3303–3311. Mann, V.M., Cooper, J.M., Daniel, S.E., Srai, K., Jenner, P., Marsden, C.D., Schapira, A.H.V., 1994. Complex I, iron, and ferritin in Parkinson's disease substantia nigra. Ann. Neurol. 36 (6), 876–881. Mantamadiotis, T., Lemberger, T., Bleckmann, S.C., Kern, H., Kretz, O., Villalba, A.M., Tronche, F., Kellendonk, C., Gau, D., Kapfhammer, J., Otto, C., 2002. Disruption of CREB function in brain leads to neurodegeneration. Nat. Genet. 31 (1), 47–54. Mark, R.J., Lovell, M.A., Markesbery, W.R., Uchida, K., Mattson, M.P., 1997. A role for 4‐hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid β‐peptide. J. Neurochem. 68 (1), 255–264. Martin-Villalba, A., Herr, I., Jeremias, I., Hahne, M., Brandt, R., Vogel, J., Schenkel, J., Herdegen, T., Debatin, K.M., 1999. CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. J. Neurosci. 19 (10), 3809–3817. Mattson, M.P., Rychlik, B., Chu, C., Christakost, S., 1991. Evidence for calcium-reducing and excitoprotective roles for the calcium-binding protein calbindin-1328k in cultured hippocampal neurons. Neuron 6 (1), 41–51. Mattson, M.P., LaFerla, F.M., Chan, S.L., Leissring, M.A., Shepel, P.N., Geiger, J.D., 2000a. Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders. Trends Neurosci. 23 (5), 222–229. Mattson, M.P., Zhu, H., Yu, J., Kindy, M.S., 2000b. Presenilin-1 mutation increases neuronal vulnerability to focal ischemia in vivo and to hypoxia and glucose deprivation in cell culture: involvement of perturbed calcium homeostasis. J. Neurosci. 20 (4), 1358–1364. Mattson, M.P., 2003. Excitotoxic and excitoprotective mechanisms. Neuromolecular Med. 3 (2), 65–94. McBride, S.M., Choi, C.H., Schoenfeld, B.P., Bell, A.J., Liebelt, D.A., Ferreiro, D., Choi, R.J., Hinchey, P., Kollaros, M., Terlizzi, A.M., Ferrick, N.J., 2010. Pharmacological and genetic reversal of age-dependent cognitive deficits attributable to decreased presenilin function. J. Neurosci. 30 (28), 9510–9522. McMillan, T.J., Leatherman, E., Ridley, A., Shorrocks, J., Tobi, S.E., Whiteside, J.R., 2008. Cellular effects of long wavelength UV light (UVA) in mammalian cells. J. Pharm. Pharmacol. 60 (8), 969–976. Mecocci, P., MacGarvey, U., Kaufman, A.E., Koontz, D., Shoffner, J.M., Wallace, D.C., Beal, M.F., 1993. Oxidative damage to mitochondrial DNA shows marked age‐dependent increases in human brain. Ann. Neurol. 34 (4), 609–616. Melov, S., Ravenscroft, J., Malik, S., Gill, M.S., Walker, D.W., Clayton, P.E., Wallace, D.C., Malfroy, B., Doctrow, S.R., Lithgow, G.J., 2000. Extension of life-span with superoxide dismutase/catalase mimetics. Science 289 (5484), 1567–1569. Michaelis, M.L., Bigelow, D.J., Schöneich, C., Williams, T.D., Ramonda, L., Yin, D., Hühmer, A.F.R., Yao, Y., Gao, J., Squier, T.C., 1996. Decreased plasma membrane calcium transport activity in aging brain. Life Sci. 59 (5–6), 405–412. Migliore, L., Coppedè, F., 2009. Environmental-induced oxidative stress in neurodegenerative disorders and aging. Mutat. Rese. Genet. Toxicol. Environ. Mutag. 674 (1), 73–84. Milner, R.E., Famulski, K.S., Michalak, M., 1992. Calcium binding proteins in the sarcoplasmic/endoplasmic reticulum of muscle and nonmuscle cells. Mol. Cell. Biochem. 112 (1), 1–13. Mishizen-Eberz, A.J., Rissman, R.A., Carter, T.L., Ikonomovic, M.D., Wolfe, B.B., Armstrong, D.M., 2004. Biochemical and molecular studies of NMDA receptor subunits NR1/2A/2B in hippocampal subregions throughout progression of Alzheimer's disease pathology. Neurobiol. Dis. 15 (1), 80–92. Mittal, M., Siddiqui, M.R., Tran, K., Reddy, S.P., Malik, A.B., 2014. Reactive oxygen species in inflammation and tissue injury. Antioxid. Redox Signal. 20 (7), 1126–1167. Mockett, R.J., Sohal, B.H., Sohal, R.S., 2010. Expression of multiple copies of mitochondrially targeted catalase or genomic Mn superoxide dismutase transgenes does not extend the life span of Drosophila melanogaster. Free Radic. Biol. Med. 49 (12), 2028–2031. Montine, T.J., Neely, M.D., Quinn, J.F., Beal, M.F., Markesbery, W.R., Roberts, L.J., Morrow, J.D., 2002. Lipid peroxidation in aging brain and Alzheimer’s disease 1, 2. Free Radic. Biol. Med. 33 (5), 620–626. Monyer, H., Sprengel, R., 1992. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256 (5060), 1217. Morley, A.A., 1995. The somatic mutation theory of aging. Mutat. Res. DNAging 338 (1–6), 19–23. Moyer, J.R., Thompson, L.T., Black, J.P., Disterhoft, J.F., 1992. Nimodipine increases excitability of rabbit CA1 pyramidal neurons in an age-and concentration-dependent manner. J. Neurophysiol. 68 (6), 2100–2109. Mu, X., He, J., Anderson, D.W., Springer, J.E., Trojanowski, J.Q., 1996. Altered expression of bcl‐2 and bax mRNA in amyotrophic lateral sclerosis spinal cord motor neurons. Ann. Neurol. 40 (3), 379–386. Muir, K.W., 2006. Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists. Curr. Opin. Pharmacol. 6 (1), 53–60. Murchison, D., Griffith, W.H., 1999. Age-related alterations in caffeine-sensitive calcium stores and mitochondrial buffering in rat basal forebrain. Cell Calcium 25 (6), 439–452. Muroyama, A., Inaka, M., Matsushima, H., Sugino, H., Marunaka, Y., Mitsumoto, Y.,

18

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

6910–6923. Simpson, J.E., Ince, P.G., Lace, G., Forster, G., Shaw, P.J., Matthews, F., Savva, G., Brayne, C., Wharton, S.B., 2010. Astrocyte phenotype in relation to Alzheimer-type pathology in the aging brain. Neurobiol. Aging 31 (4), 578–590. Snyder, E.M., Nong, Y., Almeida, C.G., Paul, S., Moran, T., Choi, E.Y., Nairn, A.C., Salter, M.W., Lombroso, P.J., Gouras, G.K., Greengard, P., 2005. Regulation of NMDA receptor trafficking by amyloid-β Nat. Neurosci. 8 (8), 1051–1058. Sommer, B., Köhler, M., Sprengel, R., Seeburg, P.H., 1991. RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67 (1), 11–19. Sonntag, W.E., Bennett, S.A., Khan, A.S., Thornton, P.L., Xu, X., Ingram, R.L., BrunsoBechtold, J.K., 2000. Age and insulin-like growth factor-1 modulate N-methyl-D-aspartate receptor subtype expression in rats. Brain Res. Bull. 51 (4), 331–338. Sorce, S., Krause, K.H., 2009. NOX enzymes in the central nervous system: from signaling to disease. Antioxid. Redox Signal. 11 (10), 2481–2504. Sorrentino, V., Volpe, P., 1993. Ryanodine receptors: how many, where and why? Trends Pharmacol. Sci. 14 (3), 98–103. Stanika, R.I., Villanueva, I., Kazanina, G., Andrews, S.B., Pivovarova, N.B., 2012. Comparative impact of voltage-gated calcium channels and NMDA receptors on mitochondria-mediated neuronal injury. J. Neurosci. 32 (19), 6642–6650. Stipanuk, M.H., 2004. Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. Annu. Rev. Nutr. 24, 539–577. Streit, J.W., Xue, Q.S., 2013. Microglial senescence. CNS Neurol. Disord. Drug Targets (Formerly Curr. Drug Targets CNS Neurol. Disord.) 12 (6), 763–767. Stutzmann, G.E., Smith, I., Caccamo, A., Oddo, S., LaFerla, F.M., Parker, I., 2006. Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer's disease mice. J. Neurosci. 26 (19), 5180–5189. Sucher, N.J., Lipton, S.A., 1991. Redox modulatory site of the NMDA receptor–channel complex: regulation by oxidized glutathione. J. Neurosci. Res. 30 (3), 582–591. Sullivan, J.M., Traynelis, S.F., Chen, H.S.V., Escobar, W., Heinemann, S.F., Lipton, S.A., 1994. Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor. Neuron 13 (4), 929–936. Sun, Y., Sukumaran, P., Schaar, A., Singh, B.B., 2015. TRPM7 and its role in neurodegenerative diseases. Channels 9 (5), 253–261. Swayne, L.A., Chen, L., Hameed, S., Barr, W., Charlesworth, E., Colicos, M.A., Zamponi, G.W., Braun, J.E., 2005. Crosstalk between huntingtin and syntaxin 1A regulates Ntype calcium channels. Mol. Cell. Neurosci. 30 (3), 339–351. Taghibiglou, C., Martin, H.G., Lai, T.W., Cho, T., Prasad, S., Kojic, L., Lu, J., Liu, Y., Lo, E., Zhang, S., Wu, J.Z., 2009. Role of NMDA receptor–dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries. Nat. Med. 15 (12), 1399–1406. Taglialatela, G., Gegg, M., Perez-Polo, J.R., Williams, L.R., Rose, G.M., 1996. Evidence for DNA fragmentation in the CNS of aged Fischer-344 rats. Neuroreport 7 (5), 977–980. Takei, K., Mignery, G.A., Mugnaini, E., Südhof, T.C., De Camilli, P., 1994. Inositol 1, 4, 5trisphosphate receptor causes formation of ER cisternal stacks in transfected fibroblasts and in cerebellar Purkinje cells. Neuron 12 (2), 327–342. Talantova, M., Sanz-Blasco, S., Zhang, X., Xia, P., Akhtar, M.W., Okamoto, S.I., Dziewczapolski, G., Nakamura, T., Cao, G., Pratt, A.E., Kang, Y.J., 2013. A (induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc. Natl. Acad. Sci. 110 (27), E2518–E2527. Tang, T.S., Tu, H., Chan, E.Y., Maximov, A., Wang, Z., Wellington, C.L., Hayden, M.R., Bezprozvanny, I., 2003. Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1, 4, 5) triphosphate receptor type 1. Neuron 39 (2), 227–239. Tang, T.S., Guo, C., Wang, H., Chen, X., Bezprozvanny, I., 2009. Neuroprotective effects of inositol 1, 4, 5-trisphosphate receptor C-terminal fragment in a Huntington's disease mouse model. J. Neurosci. 29 (5), 1257–1266. Tateno, M., Sadakata, H., Tanaka, M., Itohara, S., Shin, R.M., Miura, M., Masuda, M., Aosaki, T., Urushitani, M., Misawa, H., Takahashi, R., 2004. Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model. Hum. Mol. Genet. 13 (19), 2183–2196. Taylor, R.C., 2016. Aging and the UPR (ER). Brain Res. 1648, 588–593. Terman, A., Brunk, U.T., 1998. Lipofuscin: mechanisms of formation and increase with age. APMIS 106 (1–6), 265–276. Thibault, O., Landfield, P.W., 1996. Increase in single L-type calcium channels in hippocampal neurons during aging. Science 272 (5264), 1017. Thibault, O., Hadley, R., Landfield, P.W., 2001. Elevated postsynaptic [Ca2+] iand L-Type calcium channel activity in aged hippocampal neurons: relationship to impaired synaptic plasticity. J. Neurosci. 21 (24), 9744–9756. Thompson, L.T., Deyo, R.A., Disterhoft, J.F., 1990. Nimodipine enhances spontaneous activity of hippocampal pyramidal neurons in aging rabbits at a dose that facilitates associative learning. Brain Res. 535 (1), 119–130. Timiras, P.S. (Ed.), 2007. Physiological Basis of Aging and Geriatrics. CRC Press. Tjiattas, L., Ortiz, D.O., Dhivant, S., Mitton, K., Rogers, E., Shea, T.B., 2004. Folate deficiency and homocysteine induce toxicity in cultured dorsal root ganglion neurons via cytosolic calcium accumulation. Aging cell 3 (2), 71–76. Tollefson, G.D., 1990. Short-term effects of the calcium channel blocker nimodipine (Baye-9736) in the management of primary degenerative dementia. Biol. Psychiatry 27 (10), 1133–1142. Tosato, M., Zamboni, V., Ferrini, A., Cesari, M., 2007. The aging process and potential interventions to extend life expectancy. Clin. Interv. Aging 2 (3), 401. Toulmond, S., Tang, K., Bureau, Y., Ashdown, H., Degen, S., O'Donnell, R., Tam, J., Han, Y., Colucci, J., Giroux, A., Zhu, Y., 2004. Neuroprotective effects of M826, a reversible caspase‐3 inhibitor, in the rat malonate model of Huntington's disease. Br. J. Pharmacol. 141 (4), 689–697. Tower, J., 2000. Transgenic methods for increasing Drosophila life span. Mech. Aging Dev. 118 (1), 1–14.

Astrocytes aged in vitro show a decreased neuroprotective capacity. J. Neurochem. 101 (3), 794–805. Peters, A., Sethares, C., 2004. Oligodendrocytes, their progenitors and other neuroglial cells in the aging primate cerebral cortex. Cereb. Cortex 14 (9), 995–1007. Peterson, C., Gibson, G.E., 1983. Aging and 3, 4-diaminopyridine alter synaptosomal calcium uptake. J. Biol. Chem. 258 (19), 11482–11486. Prince, M.J., 2015. World Alzheimer Report 2015: the Global Impact of Dementia: an Analysis of Prevalence, Incidence, Cost and Trends. Privat, A.M., Gimenez-Ribotta, Ridet, J.L., 1995. Morphology of astrocytes. In: Kettenmann, H., Ransomeds, B.R. (Eds.), Neuroglia. Oxford Univ. Press, New York, pp. 3–22. Przedborski, S., Tieu, K., Perier, C., Vila, M., 2004. MPTP as a mitochondrial neurotoxic model of Parkinson's disease. J. Bioenerg. Biomembr. 36 (4), 375–379. Rao, R.V., Ellerby, H.M., Bredesen, D.E., 2004. Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ. 11 (4), 372–380. Ravikumar, B., Sarkar, S., Davies, J.E., Futter, M., Garcia-Arencibia, M., Green-Thompson, Z.W., Jimenez-Sanchez, M., Korolchuk, V.I., Lichtenberg, M., Luo, S., Massey, D.C., 2010. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol. Rev. 90 (4), 1383–1435. Rizzuto, R., Bernardi, P., Pozzan, T., 2000. Mitochondria as all‐round players of the calcium game. J. Physiol. 529 (1), 37–47. Robitaille, R., Bourque, M.J., Vandaele, S., 1996. Localization of L-type Ca2+ channels at perisynaptic glial cells of the frog neuromuscular junction. J. Neurosci. 16 (1), 148–158. Rodríguez, J.J., Yeh, C.Y., Terzieva, S., Olabarria, M., Kulijewicz-Nawrot, M., Verkhratsky, A., 2014. Complex and region-specific changes in astroglial markers in the aging brain. Neurobiol. Aging 35 (1), 15–23. Roitbak, A.I., 1970. Negative components of the direct cortical response. Neurophysiology 2 (4), 251–259. Romano, C., Van den Pol, A.N., O'Malley, K.L., 1996. Enhanced early developmental expression of the metabotropic glutamate receptor mGluR5 in rat brain: protein, mRNA splice variants, and regional distribution. J. Comp. Neurol. 367 (3), 403–412. Rothstein, J.D., 1996. Excitotoxicity hypothesis. Neurology 47 (4 (Suppl. 2)), 19S–26S. Rothstein, J.D., 2009. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann. Neurol. 65 (S1), S3–S9. Ryazanova, L.V., Rondon, L.J., Zierler, S., Hu, Z., Galli, J., Yamaguchi, T.P., Mazur, A., Fleig, A., Ryazanov, A.G., 2010. TRPM7 is essential for Mg2+ homeostasis in mammals. Nat. Commun. 1, 109. Rybalchenko, V., Hwang, S.Y., Rybalchenko, N., Koulen, P., 2008. The cytosolic N-terminus of presenilin-1 potentiates mouse ryanodine receptor single channel activity. Int. J. Biochem. Cell Biol. 40 (1), 84–97. Salminen, A., Kauppinen, A., Suuronen, T., Kaarniranta, K., Ojala, J., 2009. ER stress in Alzheimer's disease: a novel neuronal trigger for inflammation and Alzheimer's pathology. J. Neuroinflammation 6 (1), p.41. Salminen, A., Ojala, J., Kaarniranta, K., Haapasalo, A., Hiltunen, M., Soininen, H., 2011. Astrocytes in the aging brain express characteristics of senescence‐associated secretory phenotype. Eur. J. Neurosci. 34 (1), 3–11. Santo-Domingo, J., Demaurex, N., 2010. Calcium uptake mechanisms of mitochondria. Biochim. Biophys. Acta (BBA)-Bioenergetics 1797 (6), 907–912. Sasaki, T., Unno, K., Tahara, S., Kaneko, T., 2010. Age-related increase of reactive oxygen generation in the brains of mammals and birds: is reactive oxygen a signaling molecule to determine the aging process and life span? Geriatrics Gerontol. Int. 10 (s1). Sawada, M., Carlson, J.C., 1987. Changes in superoxide radical and lipid peroxide formation in the brain, heart and liver during the lifetime of the rat. Mech. Aging Dev. 41 (1), 125–137. Scarffe, L.A., Stevens, D.A., Dawson, V.L., Dawson, T.M., 2014. Parkin and PINK1: much more than mitophagy. Trends Neurosci. 37 (6), 315–324. Scheff, S.W., Price, D.A., Schmitt, F.A., DeKosky, S.T., Mufson, E.J., 2007. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68 (18), 1501–1508. Schilling, T., Eder, C., 2011. Amyloid‐β‐induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia. J. Cell. Physiol. 226 (12), 3295–3302. Schulz, J.B., Matthews, R.T., Klockgether, T., Dichgans, J., Beal, M.F., 1997. The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases. Mol. Cell. Biochem. 174 (1–2), 193–197. Severson, J.A., Finch, C.E., 1981. Striatal and cerebral cortical calmodulin in aged C57BL/ 6J mice. Soc. Neurosci. Abstr. 7, 186. Shankar, G.M., Bloodgood, B.L., Townsend, M., Walsh, D.M., Selkoe, D.J., Sabatini, B.L., 2007. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J. Neurosci. 27 (11), 2866–2875. Sheehan, J.P., Swerdlow, R.H., Miller, S.W., Davis, R.E., Parks, J.K., Parker, W.D., Tuttle, J.B., 1997. Calcium homeostasis and reactive oxygen species production in cells transformed by mitochondria from individuals with sporadic Alzheimer’s disease. J. Neurosci. 17 (12), 4612–4622. Shehadeh, J., Fernandes, H.B., Mullins, M.M.Z., Graham, R.K., Leavitt, B.R., Hayden, M.R., Raymond, L.A., 2006. Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease. Neurobiol. Dis. 21 (2), 392–403. Shi, P., Gal, J., Kwinter, D.M., Liu, X., Zhu, H., 2010. Mitochondrial dysfunction in amyotrophic lateral sclerosis. Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 1802 (1), 45–51. Shilling, D., Müller, M., Takano, H., Mak, D.O.D., Abel, T., Coulter, D.A., Foskett, J.K., 2014. Suppression of InsP3 receptor-mediated Ca2+ signaling alleviates mutant presenilin-linked familial Alzheimer's disease pathogenesis. J. Neurosci. 34 (20),

19

Journal of Chemical Neuroanatomy xxx (xxxx) xxx–xxx

R. Chandran et al.

oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones. Hum. Mol. Genet. 17 (4), 469–477. Weinert, B.T., Timiras, P.S., 2003. Invited review: theories of aging. J. Appl. Physiol. 95 (4), 1706–1716. Weiss, J.H., Hartley, D.M., Koh, J.Y., Choi, D.W., 1990. The calcium channel blocker nifedipine attenuates slow excitatory amino acid neurotoxicity. Science(Washington) 247 (4949), 1474–1477. West, A.E., Chen, W.G., Dalva, M.B., Dolmetsch, R.E., Kornhauser, J.M., Shaywitz, A.J., Takasu, M.A., Tao, X., Greenberg, M.E., 2001. Calcium regulation of neuronal gene expression. Proc. Natl. Acad. Sci. 98 (20), 11024–11031. Williams, S.M., Diaz, C.M., Macnab, L.T., Sullivan, R.K., Pow, D.V., 2006. Immunocytochemical analysis of D-serine distribution in the mammalian brain reveals novel anatomical compartmentalizations in glia and neurons. Glia 53 (4), 401–411. Wojda, U., Salinska, E., Kuznicki, J., 2008. Calcium ions in neuronal degeneration. IUBMB Life 60 (9), 575–590. Wong, P.C., Cai, H., Borchelt, D.R., Price, D.L., 2002. Genetically engineered mouse models of neurodegenerative diseases. Nat. Neurosci. 5 (7), 633–639. Wu, S., Barger, S.W., 2004. Induction of serine racemase by inflammatory stimuli is dependent on AP‐1. Ann. N. Y. Acad. Sci. 1035 (1), 133–146. Wu, S.Z., Bodles, A.M., Porter, M.M., Griffin, W.S.T., Basile, A.S., Barger, S.W., 2004. Induction of serine racemase expression and D-serine release from microglia by amyloid (-peptide. J. Neuroinflammation 1 (1), 2. Xiong, J., Verkhratsky, A., Toescu, E.C., 2002. Changes in mitochondrial status associated with altered Ca2+ homeostasis in aged cerebellar granule neurons in brain slices. J. Neurosci. 22 (24), 10761–10771. Xu, J., Kurup, P., Zhang, Y., Goebel-Goody, S.M., Wu, P.H., Hawasli, A.H., Baum, M.L., Bibb, J.A., Lombroso, P.J., 2009. Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. J. Neurosci. 29 (29), 9330–9343. Yamanaka, K., Chun, S.J., Boillee, S., Fujimori-Tonou, N., Yamashita, H., Gutmann, D.H., Takahashi, R., Misawa, H., Cleveland, D.W., 2008. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat. Neurosci. 11 (3), 251–253. Yoo, A.S., Cheng, I., Chung, S., Grenfell, T.Z., Lee, H., Pack-Chung, E., Handler, M., Shen, J., Xia, W., Tesco, G., Saunders, A.J., 2000. Presenilin-mediated modulation of capacitative calcium entry. Neuron 27 (3), 561–572. Yoshimori, T., 2007. Autophagy: paying charon's toll. Cell 128 (5), 833–836. Zündorf, G., Reiser, G., 2011. Calcium dysregulation and homeostasis of neural calcium in the molecular mechanisms of neurodegenerative diseases provide multiple targets for neuroprotection. Antioxid. Redox Signal. 14 (7), 1275–1288. Zamzow, D.R., Elias, V., Shumaker, M., Larson, C., Magnusson, K.R., 2013. An increase in the association of GluN2B containing NMDA receptors with membrane scaffolding proteins was related to memory declines during aging. J. Neurosci. 33 (30), 12300–12305. Zeng, L., Hu, C., Zhang, F., Xu, D.C., Cui, M.Z., Xu, X., 2015. FLIP and PSAP mediate presenilin 1-induced γ-secretase dependent and independent apoptosis respectively. J. Biol. Chem. jbc-M115. Zeron, M.M., Hansson, O., Chen, N., Wellington, C.L., Leavitt, B.R., Brundin, P., Hayden, M.R., Raymond, L.A., 2002. Increased sensitivity to N-methyl-D-aspartate receptormediated excitotoxicity in a mouse model of Huntington's disease. Neuron 33 (6), 849–860. Zha, X.M., 2013. Acid-sensing ion channels: trafficking and synaptic function. Mol. Brain 6 (1), 1. Zhao, W., Xie, W., Le, W., Beers, D.R., He, Y., Henkel, J.S., Simpson, E.P., Yen, A.A., Xiao, Q., Appel, S.H., 2004. Activated microglia initiate motor neuron injury by a nitric oxide and glutamate-mediated mechanism. J. Neuropathol. Exp. Neurol. 63 (9), 964–977. Zhao, X., Rosenke, R., Kronemann, D., Brim, B., Das, S.R., Dunah, A.W., Magnusson, K.R., 2009. The effects of aging on N-methyl-D-aspartate receptor subunits in the synaptic membrane and relationships to long-term spatial memory. Neuroscience 162 (4), 933–945. Żylińska, L., Gromadzińska, E., Lachowicz, L., 1999. Short-time effects of neuroactive steroids on rat cortical Ca 2+-ATPase activity. Biochim. Biophys. Acta (BBA) Mol. Cell Biol. Lipids 1437 (2), 257–264.

Tremblay, M.È., Zettel, M.L., Ison, J.R., Allen, P.D., Majewska, A.K., 2012. Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia 60 (4), 541–558. Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J.N., Rovio, A.T., Bruder, C.E., Bohlooly-y, M., Gidlöf, S., Oldfors, A., Wibom, R., Törnell, J., 2004. Premature aging in mice expressing defective mitochondrial DNA polymerase. Nature 429 (6990), 417–423. Trifunovic, A., 2006. Mitochondrial DNA and aging. Biochim. Biophys. Acta (BBA) Bioenergetics 1757 (5), 611–617. Trimmer, P.A., Swerdlow, R.H., Parks, J.K., Keeney, P., Bennett, J.P., Miller, S.W., Davis, R.E., Parker, W.D., 2000. Abnormal mitochondrial morphology in sporadic Parkinson's and Alzheimer's disease cybrid cell lines. Exp. Neurol. 162 (1), 37–50. Troost, P.W., Lahuis, B.E., Steenhuis, M.P., Ketelaars, C.E., Buitelaar, J.K., van Engeland, H., Scahill, L., Minderaa, R.B., Hoekstra, P.J., 2005. Long-term effects of risperidone in children with autism spectrum disorders: a placebo discontinuation study. J. Am. Acad. Child Adolesc. Psychiatry 44 (11), 1137–1144. Troy, C.M., Salvesen, G.S., 2002. Caspases on the brain. J. Neurosci. Res. 69 (2), 145–150. Tsai, V.W.W., Scott, H.L., Lewis, R.J., Dodd, P.R., 2005. The role of group I metabotropic glutamate receptors in neuronal excitotoxicity in Alzheimer’s disease. Neurotox. Res. 7 (1–2), 125–141. Tu, Y., Tornaletti, S., Pfeifer, G.P., 1996. DNA repair domains within a human gene: selective repair of sequences near the transcription initiation site. EMBO J. 15 (3), p.675. Tu, H., Nelson, O., Bezprozvanny, A., Wang, Z., Lee, S.F., Hao, Y.H., Serneels, L., De Strooper, B., Yu, G., Bezprozvanny, I., 2006. Presenilins form ER Ca 2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell 126 (5), 981–993. United Nations Department of Economic and Social Affairs, Population Division, 2015. World Population Ageing 2015, Report ST/ESA/SER.A/390. . http://www.un.org/ en/development/desa/population/publications/pdf/aging/WPA2015_Report.pdf. (United Nations, 2015). Urushitani, M., Sik, A., Sakurai, T., Nukina, N., Takahashi, R., Julien, J.P., 2006. Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat. Neurosci. 9 (1), 108–118. Van Damme, P., Bogaert, E., Dewil, M., Hersmus, N., Kiraly, D., Scheveneels, W., Bockx, I., Braeken, D., Verpoorten, N., Verhoeven, K., Timmerman, V., 2007. Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. Proc. Natl. Acad. Sci. 104 (37), 14825–14830. Van Es, M.A., Van Vught, P.W., Blauw, H.M., Franke, L., Saris, C.G., Andersen, P.M., Van Den Bosch, L., de Jong, S.W., van't Slot, R., Birve, A., Lemmens, R., 2007. ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study. Lancet Neurol. 6 (10), 869–877. Vance, J.E., 2014. MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond. Biochim. Biophysica Acta (BBA)- Mol. Cell Biol. Lipids 1841 (4), 595–609. Veng, L.M., Browning, M.D., 2002. Regionally selective alterations in expression of the (1D subunit (CaV 1.3) of L-type calcium channels in the hippocampus of aged rats. Mol. Brain Res. 107 (2), 120–127. Verkhratsky, A., Steinhäuser, C., 2000. Ion channels in glial cells. Brain Res. Rev. 32 (2), 380–412. Verkhratsky, A., 2005. Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol. Rev. 85 (1), 201–279. Vicini, S., Wang, J.F., Li, J.H., Zhu, W.J., Wang, Y.H., Luo, J.H., Wolfe, B.B., Grayson, D.R., 1998. Functional and pharmacological differences between recombinantNmethyl-D-aspartate receptors. J. Neurophysiol. 79 (2), 555–566. Vila, M., Ramonet, D., Perier, C., 2008. Mitochondrial alterations in Parkinson’s disease: new clues. J. Neurochem. 107 (2), 317–328. Villayandre, B.M., Paniagua, M.A., Fernández-López, A., Chinchetru, M.A., Calvo, P., 2004. Effect of vitamin E treatment on N-methyl-d-aspartate receptor at different ages in the rat brain. Brain Res. 1028 (2), 148–155. Vitek, M.P., Bhattacharya, K., Glendening, J.M., Stopa, E., Vlassara, H., Bucala, R., Manogue, K., Cerami, A., 1994. Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc. Natl. Acad. Sci. 91 (11), 4766–4770. Vosler, P.S., Brennan, C.S., Chen, J., 2008. Calpain-mediated signaling mechanisms in neuronal injury and neurodegeneration. Mol. Neurobiol. 38 (1), 78–100. Wei, H., Kim, S.J., Zhang, Z., Tsai, P.C., Wisniewski, K.E., Mukherjee, A.B., 2008. ER and

20