Major depression, cognitive dysfunction and Alzheimer's disease: Is there a link?

European Journal of Pharmacology 626 (2010) 72–82

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European Journal of Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j p h a r

Review

Major depression, cognitive dysfunction and Alzheimer's disease: Is there a link? Annerieke S.R. Sierksma ⁎, Daniel L.A. van den Hove, Harry W.M. Steinbusch, Jos Prickaerts Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Maastricht University, The Netherlands European Graduate School of Neuroscience (Euron), Maastricht, The Netherlands

a r t i c l e

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Article history: Received 31 July 2009 Received in revised form 29 September 2009 Accepted 6 October 2009 Available online 20 October 2009 Keywords: Major depression Alzheimer's disease Cognitive dysfunction Serotonergic system HPA-axis

a b s t r a c t Major depression (MD) is a severe mental disorder characterized by alterations in mood and cognition, with disease severity correlating inversely with cognition scores. Neuropathology can be found abundantly in the limbic system, which is thought to regulate affect, attention and memory. Hypothalamic–pituitary–adrenal (HPA) axis overdrive, as well as decreased serotonin levels, have often been implicated in the pathogenesis of this illness. Interestingly, there is substantial interaction between these two systems, with receptors of one system influencing the function of the other. This results in impaired neural networks, which give rise to the wide range of depressive symptoms. Recently, it has been implied that MD could serve as a risk factor for developing Alzheimer's disease (AD), with patients suffering from lifetime depression having a twofold higher chance of developing AD and exhibiting more AD-related neuropathology. Modifications in the HPAaxis and the serotonergic system may contribute to the development of cognitive decline and eventually AD. These two systems may therefore be involved in the pathogenesis of both illnesses and could provide a link between MD and AD. Obtaining more knowledge on their interactive role in the relation between MD and AD may eventually aid in the development of more effective treatment strategies. © 2009 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . Neuropathology in MD . . . . . . . . . . . . . . . . . . . MD and hypothalamus–pituitary–adrenal axis . . . . . . . . 3.1. Functional and structural alterations of HPA axis in MD 3.2. The glucocorticoid cascade hypothesis. . . . . . . . . 4. MD and the serotonergic system . . . . . . . . . . . . . . 4.1. Genetic variations of the 5HTT increase the risk for MD 5. Interaction between 5-HT and the HPA-axis . . . . . . . . . 5.1. Genetic variations interacting with the HPA-axis . . . . 6. The link between MD and AD . . . . . . . . . . . . . . . . 6.1. AD and the HPA-axis . . . . . . . . . . . . . . . . . 6.2. AD and the serotonergic system . . . . . . . . . . . 7. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . Acknowlegdements . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

Abbreviations: 5-HT, serotonin; Aβ, Amyloid-β; CRH, corticotrophin-releasing hormone; GCs, glucocorticoids; GR, glucocorticoid receptor; HPA, hypothalamus– pituitary–adrenal; MR, mineralocorticoid receptor; NFT, neurofibrillary tangles. ⁎ Corresponding author. Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Maastricht University, The Netherlands. E-mail address: [email protected] (A.S.R. Sierksma). 0014-2999/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2009.10.021

Major depression (MD) is the most common psychiatric disorder, with almost 1 in 5 people experiencing a depressive episode during their lifetime (Kessler et al., 2003). It is the fourth leading cause of global disease and disability burden and yearly 33.4 million people in Europe are suffering from this illness (WHO-Europe, 2003). Besides its affective symptoms, such as anhedonia, depressed mood, feelings of worthlessness or guilt and recurrent thoughts of death or

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suicide, the patient often exhibits symptoms like appetite/weight disturbance, fatigue, and difficulties concentrating. These symptoms could be indicative of neuroendocrine and/or neuroanatomical changes (American Psychiatric Association. Task Force on DSM-IV. and American Psychiatric Association, 2000). Apart from the well-known affective changes in patients with MD, many also exhibit a large range of cognitive deficits. Common cognitive dysfunctions include impairments in recollection memory, list learning, recall, verbal and visual memory, executive function, attention and verbal fluency (Austin et al., 2001; Castaneda et al., 2008; Hickie et al., 2005; MacQueen et al., 2003; Ravnkilde et al., 2002; Sheline et al., 1999). Severity of the depressive complaints can be correlated with cognition scores (Bassuk et al., 1998; Yaffe et al., 1999). It has become apparent that underlying systemic alterations can dramatically influence our affect and cognitive abilities. For example, alterations in the hypothalamus–pituitary–adrenal (HPA) axis, as can be seen in patients with Cushing's syndrome, cause severe depressive complaints as well as many neuroendocrine changes also seen in MD (Kelly et al., 1983; Shibli-Rahhal et al., 2006). Likewise, the serotonergic system has been implied in the pathogenesis of MD, and antidepressants targeting this system have been shown to be very effective. This review will discuss how the HPA-axis and the serotonergic system can influence the cognitive decline seen in MD patients, both independently as well as interactively. In addition, it argues the possibility that MD could serve as a risk factor for Alzheimer's disease (AD), which is renowned for its progressive cognitive deterioration. The role of the HPA-axis and the serotonergic system in the development of cognitive decline in AD is examined as well as the relation between MD and AD.

2. Neuropathology in MD The wide range of symptoms in MD suggests that many different brain regions are involved in its etiology. Particularly the limbic system has received much attention, since this system is thought to govern our affective behaviour and is involved in learning and memory processes. Its main structures include the hippocampus, amygdala and prefrontal cortex (PFC), all of which are highly interconnected. The hippocampus is known as the primary memory structure, necessary for declarative memory, or remembering facts. The amygdala is thought to control emotional processing, and is particularly involved in fear and aggression. Due to the high level of reciprocal connections, the hippocampus and amygdala are thought to regulate memory by modulating attention and consolidation processes, as reviewed in (Phelps, 2004; Roozendaal et al., 2009). The PFC is thought to exert topdown control over all emotions, thoughts and actions (Arnsten, 2009). Imaging studies have shown abnormalities in structure and function within these areas in MD patients, although inconsistent results have been reported. Results are often confounded by the age and gender of the subjects, the number of depressive episodes, use of medication, definition of region of interest etc. (see (Hamilton et al., 2008; Konarski et al., 2008)). The hippocampus is one of the key structures in the brain for learning and memory processes and alterations in its structure and function have been unequivocally established in patients with MD. For example, MD has been associated with increased hippocampal glucose metabolism (Aihara et al., 2007) as well as reductions in hippocampal volume (Bell-McGinty et al., 2002; Bremner et al., 2000; Hickie et al., 2005; Janssen et al., 2004; Sheline et al., 2003, 1999, 1996). Moreover, clinical variables such as disease duration and time spent untreated correlated negatively with hippocampal volume (Bell-McGinty et al., 2002; Colla et al., 2007; MacQueen et al., 2003; Sheline et al., 2003, 1999, 1996). In addition, the hippocampal volume

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reductions as seen in MD correlated significantly with cognitive dysfunction and memory decrements (Hickie et al., 2005). It remains uncertain whether smaller hippocampal volume could be a predisposition for developing MD, or whether it is a consequence of the disease process. Volumetric reductions have been reported as early as the first depressive episode (Frodl et al., 2002), although others are not able to replicate these results (MacQueen et al., 2003). MacQueen and colleagues (2003) found that recollection memory was comprised as early as the first episode. Reductions in hippocampal volume, however, were thought to develop early in the disease process but not until multiple episodes have occurred. Hippocampal atrophy is assumed to be caused by a reduction in neuropil, since no cell loss has actually been reported in MD. A decrease in the size of pyramidal and granular neurons, however, has been reported (Stockmeier et al., 2004). Another limbic structure, the amygdala, is particularly important for the perception and memory of emotions. It has many reciprocal connections with the hippocampus (Aggleton, 1986; Pikkarainen et al., 1999) and it is thought that memory is shaped by an orchestrated interplay between these structures (as reviewed in (RichterLevin, 2004)). Due to the high level of interconnectivity between the amygdala and the hippocampus, it was assumed that MD would also result in aberrant amygdalar structure and function. However, some degree of controversy remains about changes in amygdalar volume in MD. Some report volumetric decreases, which inversely correlated with the number of depressive episodes or degree of hippocampal volume loss (Kronenberg et al., 2009; Sheline et al., 1999), while others claim that current depression leads to an increased amygdala volume, which could be correlated to disease severity (van Eijndhoven et al., 2009). A recent meta-analysis concluded that unmedicated MD patients exhibit a significant decrease in amygdala volume, while medicated patients show an increase (Hamilton et al., 2008). With respect to its function, it has been reported that MD patients have higher glucose metabolism in the amygdala, which was positively correlated with negative affect, stress plasma cortisol levels (indicative of neuroendocrine stress) and severity of current depressive complaints (Abercrombie et al., 1998; Drevets et al., 1992, 2002). MD is also associated with a decreased cerebral blood flow in the amygdala, which was inversely correlated with the severity of the depressed mood (Perico et al., 2005). The PFC is thought to regulate and fine-tune all cognitive functions. Based on its anatomical connectivity and functional differentiation, the PFC can be divided into several subregions, such as the orbitofrontal cortex, the ventromedial PFC and the dorsolateral PFC (as reviewed in (Maletic et al., 2007) and (Zald, 2007)). The ventromedial PFC is thought to be involved in regulating affective behaviour, as can be seen by its projections to the hypothalamus and its dense reciprocal connections with the amygdala. In contrast, the dorsolateral PFC is associated more with cognitive or executive functions, since it is highly connected to the orbitofrontal cortex and the hippocampus (Koenigs and Grafman, 2009; Wall and Messier, 2001). It might not be surprising that the structure and function of the PFC is also altered in MD patients. The ventromedial PFC and the orbitofrontal cortex exhibit hyperactivity, while the dorsolateral PFC is hypoactive and associated with more negative emotions (Aihara et al., 2007; Biver et al., 1994; Galynker et al., 1998; Perico et al., 2005). In addition, hyperactivity in the orbitofrontal cortex can be directly correlated with anxiety levels and overall cognitive functioning (Perico et al., 2005) and reductions in volume and neuronal size have been reported in MD patients in the same area (Bremner et al., 2002). The exact mechanism underlying the changes seen in structure and function of various parts of the limbic system in MD, remains to be elucidated. However, several mechanisms have been proposed, such as dysfunctions in the HPA-axis or the serotonergic system.

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3. MD and hypothalamus–pituitary–adrenal axis The HPA-axis regulates the stress response by secreting specific stress hormones, or glucocorticoids. This stress response prepares the body and the brain for an adequate reaction to the stressor. Apart from its peripheral effects, the HPA also impacts the central nervous system. The secretion of glucocorticoids is orchestrated by the paraventricular nucleus (PVN) of the hypothalamus. In response to stress, the parvocellular neurons located in this nucleus synthesize and secrete corticotrophin-releasing hormone (CRH) into the pituitary portal system. This causes the anterior pituitary to release adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal glands to produce glucocorticoids (cortisol in humans, corticosterone in rodents). The release of glucocorticoids results in a stress response in the body, thereby altering energy metabolism and immunity. The glucocorticoids regulate negative feedback to the hypothalamus and pituitary by diminishing the secretion of CRH and ACTH. The hippocampus also has an inhibitory effect on the HPA-axis (see (Praag et al., 2004)). Levels of circulating glucocorticoids are monitored by two types of receptors: the mineralocorticoid receptor and the glucocorticoid receptor. The mineralocorticoid receptor is a high-affinity receptor and located almost exclusively in the hippocampus. Under physiological conditions, basal levels of circadian glucocorticoids almost completely occupy these mineralocorticoid receptors, thereby giving negative feedback to the HPA-axis. Under stress or during circadian peaks, the low-affinity glucocorticoid receptors become activated and exert their negative feedback (Joels, 2006). Glucocorticoid receptors are located throughout the brain, but are most dense in the hippocampus, cortex, thalamus, hypothalamic PVN and the dorsal raphe nucleus (Harfstrand et al., 1986; Reul and de Kloet, 1986). 3.1. Functional and structural alterations of HPA axis in MD A substantial load of evidence has shown that the HPA-axis is dysregulated in MD. Indeed, multiple clinical studies have indicated that patients with MD show higher baseline levels of cortisol in plasma, serum, cerebrospinal fluid and urine (Carroll et al., 1976a,b; Gold et al., 1986; Juruena et al., 2006; Pfohl et al., 1985). In the dexamethasone-suppression test, designed to assess HPA-responsivity, MD patients are less able to downregulate the stress response, which is indicative of dysfunctional feedback mechanisms (Juruena et al., 2006; Kunugi et al., 2006). In addition, ACTH levels are elevated at baseline and after dexamethasone administration (Kalin et al., 1982; Pfohl et al., 1985; Roy et al., 1986), although these results were not always replicated (Posener et al., 2000). The combined dexamethasone/CRH test, which pretreats a person with dexamethasone before administrating CRH, was designed to increase sensitivity in measuring abnormal HPA-axis function (Heuser et al., 1994). This test also demonstrated a significantly increased cortisol release in depressed patients (Bardeleben and Holsboer, 1989; Holsboer-Trachsler et al., 1991; Kunugi et al., 2006). Higher levels of glucocorticoids are thought to occur downstream from excessive CRH secretion. It has in fact been demonstrated that MD patients have a pronounced elevation of CRH in their cerebrospinal fluid (Banki et al., 1987; Nemeroff et al., 1984; Risch et al., 1992) and a higher expression of CRH mRNA in the PVN (Raadsheer et al., 1995). Interestingly, suicide victims showed a 23% decrease in CRH binding sites in the frontal cortex (Nemeroff et al., 1988), which confirms the expected downregulation of CRH receptors in the face of CRH hypersecretion. 3.2. The glucocorticoid cascade hypothesis The negative feedback loop in which high levels of glucocorticoids suppress the production of CRH and ACTH is an important mech-

anism. Dysfunctional feedback may cause excessive responsiveness of the HPA-axis, which can have detrimental effects on both the body and brain. This is one of the theories in the etiology of depression, where prolonged exposure to high levels of glucocorticoids, due to chronic stress, damages the hippocampus and thus results in a downregulation of glucocorticoid receptors. This disables proper negative feedback to the HPA-axis. The subsequent disinhibition of the hypothalamus will in turn result in more glucocorticoid production. Subsequently, more glucocorticoid receptors will be downregulated and eventually compromise hippocampal neurons and projections, ultimately resulting in a vicious cycle. All physical, affective and cognitive changes in MD could thus be regarded as a consequence of this dysfunctional HPA-axis. This theory is known as the ‘glucocorticoid cascade hypothesis of MD’ (Sapolsky et al., 1986). In addition to an indirect receptor downregulation due to damage, it has lately become clear that the glucocorticoid receptor is directly downregulated and decreased in function in depressed patients (as reviewed in (Pariante, 2004)), which negatively impacts the negative feedback loop. Evidence for this hypothesis has been provided by the effects of chronic corticosterone treatment, which was shown to lead to a downregulation of glucocorticoid receptors in the CA1 and CA3 area of the hippocampus and a reduction in glucocorticoid and large CA3 cells (Sapolsky et al., 1985). In addition, chronic unpredictable stress, causing high levels of circulating glucocorticoids, was implied to decrease the volume of the CA3 region, and led to dendritic atrophy in CA3 pyramidal neurons (Joels et al., 2004; Magarinos et al., 1996). Furthermore, it decreased neurogenesis and impaired long-term potentiation, a cellular substrate for memory (Alfarez et al., 2003; Gerges et al., 2001; Joels et al., 2004; Pavlides et al., 2002). Since the integrity of the hippocampal network becomes comprised due to high levels of glucocorticoids, it is not surprising that its function is also altered. Elevated plasma cortisol levels have been related to the cognitive impairments seen in MD patients (Van Londen et al., 1998). Acutely elevated cortisol levels in healthy volunteers also resulted in impairment in declarative memory and spatial thinking tasks (Kirschbaum et al., 1996). Moreover, increased cortisol levels in healthy elderly correlated negatively with explicit and declarative memory and selective attention performance (Lupien et al., 1994; Lupien et al., 2005). Interestingly, all cognitive deficits that occurred as a consequence of increased glucocorticoids are highly specific for hippocampal or prefrontal dysfunction. The distribution of the glucocorticoid receptor is not restricted to the hippocampus, but can also be found in other parts of the limbic system (Honkaniemi et al., 1992; Meaney and Aitken, 1985). Indeed, acute glucocorticoid administration has also shown to impair spatial working memory, implying PFC dysfunction (Young et al., 1999). Amygdalar memory can also be altered by glucocorticoids, although in an acute setting this is not necessarily detrimental (Lupien et al., 2005; Prickaerts and Steckler, 2005). For example, memory for emotionally arousing stimuli was enhanced when cortisol was administered before acquisition (Buchanan and Lovallo, 2001; Rimmele et al., 2003). Similarly, administration of the corticosteroid synthesis inhibitor metyrapone blocked long-term declarative memory for emotionally arousing stimuli (Maheu et al., 2005). Thus chronic increased levels of glucocorticoids can negatively alter the functional integrity of limbic structures and affect the entire limbic regulation of cognition. 4. MD and the serotonergic system Another system that has been implicated in the etiology of depression is the monoaminergic system. The ‘monoamine hypothesis of depression’ states that MD is caused by a decrease of monoamines in the brain, i.e. serotonin and noradrenaline. This theory was based on the discovery that drugs altering central noradrenaline and serotonin (5-hydroxytryptamine (5-HT)) levels had antidepressive effects.

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Particularly the serotonergic system has received much attention in light of depressive research. The neurotransmitter 5-HT is synthesized from the essential amino acid L-tryptophan in the serotonergic neurons in the raphe nuclei, located in the brain stem. From here, 5-HT is transported throughout the brain, with highest fiber densities in the hippocampus, hypothalamus and amygdala (Jacobs and Azmitia, 1992; Steinbusch, 1981, 1984). There are numerous types of 5-HT receptors, but the 5-HT1A, 5-HT2A and 5-HT2C receptor have been targeted mostly in MD and antidepressant research and are thought to be involved regulating both in depression, anxiety and cognition (see (Lanfumey et al., 2008; Meltzer et al., 1998)). By interacting with the other neurotransmitter systems, e.g. the cholinergic system, 5-HT can influence several memory and learning processes. In fact, 5-HT modulates many cellular and synaptic functions necessary for proper memory and learning, such as dendritic and synaptic outgrowth and neurogenesis (as reviewed in (Gaspar et al., 2003). The 5-HT1A receptor is expressed both pre- and postsynaptically. It is most densely expressed in the raphe nucleus, the limbic system and the cortex. The 5-HT1A receptors in the dorsal raphe nucleus are mainly somatodendritic autoreceptors, thereby inhibiting the serotonergic neurons of the dorsal raphe nucleus. In the hippocampus they are mainly located postsynaptically, where they mainly inhibit the pyramidal neurons of the CA1 subregion of the hippocampus (Burnet et al., 1995; DeFelipe et al., 2001; Jacobs and Azmitia, 1992; Martin and Humphrey, 1994). Hippocampal activation of the 5-HT1A receptor is thought to be detrimental to learning abilities, most probably through its interaction with acetylcholine (Buhot et al., 2000). By using functional imaging, depressive patients were shown to have decreased binding of the 5HT-1A receptor in the raphe nuclei and limbic system (Drevets et al., 1999). These results were confirmed by Sargent et al. (2000), who also indicated reduced binding in frontal and temporal cortices. Messenger RNA levels of 5-HT1A receptor were also decreased in the hippocampus and dorsolateral PFC due to depression (Lopez-Figueroa et al., 2004). Brains of depressed suicide victims additionally showed decreased binding capacity of the 5-HT1A receptors in the raphe nuclei and hippocampus (Arango et al., 2001; Boldrini et al., 2008; Lopez et al., 1998). However, alterations in actual 5HT1A receptors are still under discussion, since some have also reported increases in the raphe nuclei and the ventrolateral PFC of depressed suicides (Arango et al., 1995; Stockmeier et al., 1998). The 5-HT2A receptor is located postsynaptically and most dense in the cortex and to a lesser extent in the limbic regions, while none are located in the raphe. It is implied to additionally regulate the release of other neurotransmitters (Burnet et al., 1995; Martin and Humphrey, 1994). Of interest is the discovery that activation of the 5-HT2A receptor by agonist 8-OH-DPAT can desensitize the 5-HT1A receptor in the hippocampus, while the number or the affinity of 5-HT1A receptor sites stayed unchanged (Hensler and Truett, 1998). The 5-HT2C receptor is also a postsynaptic receptor, which can be found primarily in the cortex and to a lesser extent in the amygdala and the CA1 and DG regions of the hippocampus (Martin and Humphrey, 1994). This receptor is said to be involved in long-term potentiation (Tecott et al., 1998). Alterations in 5-HT2 receptors in depressed patients are still a matter of debate. 5-HT2 receptor binding in blood platelets was reported to be elevated (Arora and Meltzer, 1989a), as were the postsynaptic binding sites in the frontal cortex of suicide victims (Arora and Meltzer, 1989b; Mann et al., 1986; Stanley and Mann, 1983). However, others report lower levels of 5-HT2 receptor binding with reductions as high as 76% in the frontal cortex and other cortical regions of MD patients (Yates et al., 1990; Yatham et al., 2000). Apart from the serotonergic receptor, there is also a 5-HT transporter (5-HTT), which is located at the nerve terminal of the presynaptic neuron and is responsible for clearing 5-HT from the synaptic cleft. It is expressed abundantly in the raphe nucleus and in lower

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concentrations in the limbic system. It is the main site of action for selective 5-HT reuptake inhibitors (SSRIs). Post-mortem analysis of depressed suicide victims confirmed reduced mRNA levels of the 5HTT, although the expression per neuron was upregulated (Arango et al., 2001) as well as reduced transporter binding in the PFC, particularly in the ventrolateral PFC (Arango et al., 1995). During the last decade it has been postulated that the antidepressant effects of MD medication is dependent on an increase of neurogenesis in the hippocampus (Santarelli et al., 2003), the latter in which neurotrophic factors such as brain-derived neurotrophic factor (BDNF) are thought to play a key role (see (Duman and Monteggia, 2006; Mattson et al., 2004)). There is a high degree of interaction between BDNF and the serotonergic system. For instance, serotonergic sprouting can be promoted by BDNF (Mamounas et al., 1995), and BDNF transcription can be generated by activation of the 5-HT receptors via cAMP-response-element-binding protein (CREB) (Mattson et al., 2004). Interestingly, reduced BDNF protein levels have been found in the hippocampus and PFC in the post-mortem brains of suicide victims (Karege et al., 2005). In rats, chronic stress decreased the expression of mRNA BDNF (Smith et al., 1995) and BDNF protein (Xu et al., 2006) in the hippocampus. Moreover, having a single nucleotide polymorphism in the coding exon of BDNF i.e. carrying the methione (Met)-BDNF allele, is associated with depression and significantly reduced hippocampal volumes in depressed patients (Frodl et al., 2007; Hwang et al., 2006). Of therapeutic interest in the fact that in preclinical studies antidepressant treatment has shown to significantly improve BDNF levels (reviewed in (Duman and Monteggia, 2006)). 4.1. Genetic variations of the 5HTT increase the risk for MD Over the past decade, more attention has been given to the possibility of genetic contributions to the etiology of MD. Even though no pure genetic cause for MD has been found to date, there have been indications for a genetic vulnerability. More specifically, a polymorphism was found in the regulatory region of the 5-HTT protein, also named the 5-HTT-linked polymorphic region (5-HTTLPR) (Lesch et al., 1996). The short and long alleles in the 5-HTTLPR have been shown to alter 5-HTT transcription. The short variant of the polymorphism reduces the expression of the 5HT transporter, while the long variant nearly doubles it. The 5-HTTLPR polymorphism has been associated with both anxiety and depressive disorders (Lesch et al., 1996, 1999). In fact, experiencing a stressful life event in combination with having a short allele, predicted the development of MD and increased the severity of depressive symptoms and suicidal thoughts or attempts (Caspi et al., 2003). In addition, being homozygous for the short allele decreases memory performance in elderly (O'Hara et al., 2007), and the interaction between MD diagnosis and the 5-HTTLPR polymorphism was associated with a decrease in hippocampal volume (Frodl et al., 2004). Furthermore, carrying the short allele induces hyperreactivity of the amygdala in response to fearful stimuli (Hariri et al., 2002). Canli and colleagues (2005), on the other hand, suggest that the amygdala is not hyperreactive in the face of negative stimuli, but rather that it has a decreased reactivity to neutral stimuli. This implies that carrying the 5-HTTLPR short allele can greatly alter emotional regulation in general, rather than it being specific to negative emotions (Canli et al., 2005). 5. Interaction between 5-HT and the HPA-axis Even though the HPA-axis and the serotonergic system have been implicated separately in the pathogenesis of MD, many reciprocal connections exist between the two systems. Accordingly, alterations in the HPA-axis also have an effect on the serotonergic system and vice versa.

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On a structural level, it has been shown that CRH immunoreactivity can be found in the serotonergic raphe nuclei and many of the limbic structures (Sakanaka et al., 1987; Valentino et al., 2001). Actually, in depressed suicide men CRH immunoreactivity is increased with approximately 40% in the raphe nuclei of the midbrain (Austin et al., 2003). On a functional level, it has been demonstrated in vitro that administrating CRH swiftly elevates the firing rates of serotonergic neurons in the dorsal raphe nucleus (Lowry et al., 2000). Similarly, acute stress activates the CRH receptors which resulted in an increased release of 5-HT from the central nucleus of the amygdala (Mo et al., 2008). High levels of corticosterone, induced by chronic stress, decreased 5-HT1A receptor binding and mRNA levels in the hippocampus (Bagdy et al., 1989; Lopez et al., 1998), but substantially increased mRNA levels in the frontal cortex (Morley-Fletcher et al., 2004). Depletion of glucocorticoids caused by adrenolectomy significantly increased 5-HT1A receptor density in the hippocampus and the raphe nuclei, which was restored by corticosterone replacement (De Kloet et al., 1986; Mendelson and McEwen, 1992). Moreover, corticosteroids also seem to alter 5-HT1A transcription, since its mRNA levels were highly increased after adrenolectomy (Zhong and Ciaranello, 1995). Adrenolectomy has further shown to decrease 5-HT turnover rate in the hippocampus (De Kloet et al., 1982; Van Loon et al., 1981). Further, the 5-HT precursor L-tryptophan was significantly diminished following dexamethasone administration (Maes et al., 1990a; Maes et al., 1990b). Alternatively, the 5-HT metabolite tryptophan hydroxylase activity was enhanced by high levels of CRH (Singh et al., 1992). The serotonergic system is also able to influence the HPA-axis. Activation of the 5-HT1A and 5-HT2 receptors has been shown to increase corticosterone levels in rats as well as in humans (Fuller and Snoddy, 1990; Lesch et al., 1990). However, administrating the 5HT1A agonist ipsapirone in MD patients actually diminishes the ACTH and cortisol response, indicating ineffective interaction between the 5-HT system and the HPA axis (Lesch et al., 1990). Depleting the hypothalamus from 5-HT using a neurotoxin in fact heightened the dexamethasone suppression of the HPA-axis (Feldman and Weidenfeld, 1991). In the PVN serotonergic axons have been found to directly innervate CRH immunoreactive neurons (Michelsen et al., 2008; Michelsen et al., 2007). Moreover, 5-HT1A and 5-HT2A receptors are expressed and co-localized in these neurons, thereby having the ability to alter HPA output directly (Liposits et al., 1987; Zhang et al., 2004). This was shown by the infusion of the 5-HT1A agonist 8-OHDPAT into the PVN which elevated ACTH release. The reaction could be completely blocked by the 5-HT1A antagonist WAY100635 (Osei-Owusu et al., 2005). The inhibitory effect of the 5-HT1A receptor is regulated by the 5-HT2A receptor. Activating this receptor led to a desensitization of the 5-HT1A receptor, resulting in a decreased ACTH secretion downstream (Zhang et al., 2004). Interestingly, it can be seen that activation of the 5-HT1A receptor can have a dual effect depending on its location. In the CA1 region of the hippocampus both the 5-HT1A receptor and the glucocorticoid receptor can be found abundantly (Burnet et al., 1995; Joels, 2006). Moreover, it appears that reducing 5-HT levels in the hippocampus by using the neurotoxin 5,7-dihydroxytryptamine, also significantly reduces glucocortiocoid mRNA expression levels in the dentate gyrus, CA1 and CA2 (Seckl and Fink, 1991). Activation of the 5-HT1A receptor hyperpolarizes the CA1 neurons (Andrade and Nicoll, 1987), and can thereby exert a direct effect on the negative feedback from the hippocampus to the HPA-axis. It should be noted that the mineralocorticoid receptor is able to attenuate this 5-HT1A induced hyperpolarization, whereas the glucocorticoid receptor is not (Beck et al., 1996). Due to the chronically elevated levels of glucocorticoid, cortisol will preferably bind to the glucocorticoid receptor over the

mineralocorticoid receptor (Joels, 2006), making it unlikely that the serotonergic inhibition of CA1 neurons will be lifted. On the other hand, activation of the 5-HT1A receptor in the PVN directly inhibits the HPA-axis. However, alterations in 5-HT1A binding, as exhibited in MD patients, can modify the communication of the serotonergic system with the HPA axis. 5.1. Genetic variations interacting with the HPA-axis Interestingly, it appears that polymorphisms associated with a higher chance of developing an MD episode, also influence the HPA axis. For example, being homozygous for the short allele of the 5-HTT gene, increases morning cortisol levels, and the interaction of these factors is associated with cognitive decline, hippocampal volume decreases and a higher vulnerability for subsequent depressive episodes (Goodyer et al., 2009; O'Hara et al., 2007). In addition carrying the short allele and having a family history of MD or a personal history of stressful life events, significantly increases cortisol response after being faced with a stressor (Alexander et al., 2009; Gotlib et al., 2008). Further, it has been demonstrated that polymorphisms in the glucocorticoid receptor unfavorably alter HPA-axis functioning (as reviewed in (Derijk and de Kloet, 2008)). If these polymorphisms are also combined with adverse experiences during childhood, the severity of depressive symptoms is enhanced (Bet et al., 2009). Taken together, it is clear that there is high level of interaction between the glucocorticoid and the monoaminergic hypothesis of MD. Since both systems alter proper functioning of the limbic system, it is likely that they exacerbate each other to cause the cognitive and emotional disturbances that can be seen in MD. 6. The link between MD and AD It has been demonstrated that there is a link between depressive complaints and the risk of cognitive decline during aging. More specifically, it appears that higher levels of depressive symptoms lead to a more rapid decline of global cognition (Bierman et al., 2005; Chodosh et al., 2007; Hickie et al., 2005; Raji et al., 2007; Rapp et al., 2006; Wilson et al., 2004). In addition, specific traits such as negative affect and distress proneness seemed to correlate inversely with cognitive decline (Geerlings et al., 2000; Wilson et al., 2006). Recently it has been postulated that MD could also serve as an independent risk factor for developing AD (Devanand et al., 1996; Fernandez Martinez et al., 2008; Geerlings et al., 2000, 2008; Green et al., 2003; Grunblatt et al., 2009; Kessing and Andersen, 2004; Modrego and Ferrandez, 2004; Morgan et al., 2007; Ownby et al., 2006; Yaffe et al., 1999), possibly by reducing the brains ‘reserve capacity’ (Geerlings et al., 2000). In fact, according to a meta-analysis, having a lifetime of depressive episodes increases the chance of developing AD by at least twofold (Ownby et al., 2006). Some found that this effect was influenced by early onset of depressive complaints (Geerlings et al., 2008), a history of depressive episodes (Kessing and Nilsson, 2003; Yaffe et al., 1999), or education, with only those with higher levels of education having an increased risk of developing AD (Geerlings et al., 2000). Interestingly, AD patients with a history of MD show increased numbers of neurofibrillary tangles and amyloid plaques, the neuropathological hallmarks of AD, in the hippocampus. When these patients were suffering from MD at the time the clinical AD diagnosis was made, the presence of these hallmarks increased even further (Rapp et al., 2006). In addition, MD patients have lower amyloid-β (Aβ)42 plasma levels, which normally is a biomarker for the onset of AD (van Oijen et al., 2006). Furthermore, using 2-(1-{6-[(2-[18F] Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to amyloid plaques and neurofibrillary tangles, with positron emission tomography (PET) in MD patients indicated that more severe depressive complaints correlated with the

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presence of these hallmarks in the medial temporal lobe (Lavretsky et al., 2009). Even though these studies imply that MD could serve as a risk factor for AD, the precise mechanisms underlying this development remain uncertain. Possibly, the HPA-axis and serotonergic system could play a pivotal role in this respect.

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promoter region of APP and BACE. In this case, the effects on tau would happen downstream from the changes in Aβ (Green et al., 2006). Yet again, others claim that the interaction between abnormal HPA-axis functioning and AD neuropathology is mediated via the CRH receptor (Kang et al., 2007; Lee et al., 2009; Rissman et al., 2007). 6.2. AD and the serotonergic system

6.1. AD and the HPA-axis It is important to realize that AD patients exhibit chronically elevated cortisol and ACTH levels and markedly higher levels of CRH mRNA levels in the hypothalamic PVN compared to healthy controls, indicative of disturbance in HPA-axis homeostasis (Laske et al., 2009; Raadsheer et al., 1995; Weiner et al., 1997). In addition, higher glucocorticoid levels were associated with more rapid cognitive decline (Weiner et al., 1997). Elgh and colleagues (2006) indicated that high levels of cortisol after a dexamethasone suppression test combined with lower hippocampal volumes significantly decreased verbal and spatial memory abilities in AD patients. There appears to be an interaction between HPA-axis dysfunction and the neuropathological hallmarks of AD. For example, elevated cortisol levels in AD patients are associated with alterations in Aβ42 and phosphorylated tau concentrations in cerebrospinal fluid (Laske et al., 2009). Similar results have been found in animal models of AD. Several mouse models of AD, i.e. Tg2576, 3xTg-AD and APPV717I-CT100, were subjected to chronic stress, which resulted in increased corticosterone levels, more reactive astrocytes, higher amyloid plaque deposition, higher levels of interstitial Aβ40 and Aβ42, and a down-regulation of the Aβ degrading enzyme MMP-2 (Dong et al., 2004, 2008; Green et al., 2006; Jeong et al., 2006; Kang et al., 2007; Lee et al., 2009). In addition, increased levels of the glucocorticoid receptor and the CRH-1 receptor were observed, as well as a decrease in dendritic arborization of cortical neurons and a reduction in BrdU-positive cells in the DG (Dong et al., 2008; Lee et al., 2009). Importantly, it appears that there was a strong positive correlation between the number of amyloid plaques and corticosterone levels as well as with the expression of glucocorticoid receptors in the hippocampus (Dong et al., 2008). Moreover, chronic stress in AD mice resulted in memory deficits (Dong et al., 2004; Jeong et al., 2006). Rats with a history of chronic unpredictable stress also showed increases in the amyloid precursor protein (APP), the β-site APPcleaving enzyme (BACE) and the C-terminal fragment 99 (C99), all favoring the production of neurotoxic Aβ peptides, which was exacerbated by glucocorticoid treatment. On a behavioural level deficits in spatial memory and high levels of anxiety were observed under these conditions (Catania et al., 2009). Increases in Aβ42 levels after glucocorticoid administration were also seen in macaque nonhuman primates (Kulstad et al., 2005). On a cellular level, similar results were obtained. Administering glucocorticoids resulted in an elevated secretion of Aβ40 and Aβ42 peptides, their precursors APP and C99 and their cleaving enzyme BACE (Green et al., 2006; Sotiropoulos et al., 2008). Glucocorticoids are able to make neurons more vulnerable for Aβ-induced neurotoxicity, by enhancing intracellular calcium levels, increasing oxidative stress, decreasing levels MMP-2 and by down-regulating nuclear NF-κB (Abraham et al., 2000; Lee et al., 2009; Yao et al., 2007). With regard to the formation of aberrant tau protein, it appears that both chronic and acute stress lead to an increase in tau phosphorylation (Jeong et al., 2006; Lee et al., 2009; Rissman et al., 2007). This was also seen when tau-expressing cells are treated with glucocorticoids (Sotiropoulos et al., 2008). It is clear that increased levels of glucocorticoids increase the secretion of Aβ peptides and the phosphorylation of tau. However, some propose that these alterations are mediated via the glucocorticoid receptor and the glucocorticoid-responsive element in the

With regards to the serotonergic system, it appears that it also becomes comprised due to the degenerative nature of AD. Postmortem AD brains show more neurofibrillary tangles in the dorsal raphe nucleus and a reduction in neuron number and large neuron density compared to healthy controls (Curcio and Kemper, 1984; Hendricksen et al., 2004; Lyness et al., 2003; Yamamoto and Hirano, 1985). The behavioural changes that can be seen in AD patients, may be, at least in part, attributable to losses in the serotonergic system (Palmer et al., 1987). Moreover, the 5-HTTLPR polymorphism has also been proposed as a risk-factor for late-onset AD (Li et al., 1997; Mossner et al., 2000). A decrease was found in 5-HT1A and 5-HT2A receptor binding sites in AD post-mortem and living brains, specifically in frontal, temporal and the parietal lobes, the amygdala and the hippocampus, with losses up to fifty percent (Arai et al., 1984; Bowen et al., 1983; Cross et al., 1984; Crow et al., 1984; Jansen et al., 1990; Middlemiss et al., 1986; Palmer et al., 1988; Perry et al., 1984; Reynolds et al., 1984; Truchot et al., 2008). A reduction in 5-HTT binding sites in the frontal and temporal lobes as well as in the raphe nuclei, hippocampus and several subcortical structures was also found (Chen et al., 1996; D'Amato et al., 1987; Ouchi et al., 2009; Tejani-Butt et al., 1995; Thomas et al., 2006). Neither disease severity, plaque load, nor cortical pyramidal neuron loss could be correlated to 5-HT1a receptor losses (Palmer et al., 1987). In contrast, 5-HT1A binding in the hippocampus was associated with progressive cognitive dysfunction. In addition, 5HT1A binding could be negatively correlated with FDDNP binding in the hippocampus (Kepe et al., 2006). 5-HT2 binding in the cortex can be correlated with neurofibrillary tangle formation (Perry et al., 1984). Moreover, decreases in 5-HT binding in the temporal cortex, was associated with levels of general cognition as measured by the Mini-Mental State Examination (Chen et al., 1996). Besides the structural and functional changes in the serotonergic system of AD patients, a link exists between 5-HT and the production of Aβ. Serotonin increases the release of non-amyloidogenic APP via 5-HT2A and 2C receptors, thereby disfavoring the formation of neurotoxic Aβ (Nitsch et al., 1996). According to Lezoualc'h and Robert (2003), this effect was mediated via the 5-HT4 receptor, which is expressed highly in the limbic system (Eglen et al., 1995). In AD patients a reduction in 5-HT4 receptor binding sites in the hippocampus and the frontal cortex has been observed (Reynolds et al., 1995). Via these mechanisms a reduction in 5-HT levels could potentially alter the cleavage of APP facilitating Aβ production. Both effects could be blocked by receptor-specific antagonists (Lezoualc'h and Robert, 2003; Nitsch et al., 1996). Antidepressants can significantly alter Aβ production as well. Treating the 3xTgAD mouse model of AD with the SSRI paroxetine decreased levels of extracellular Aβ40, intraneuronal Aβ, and tau immunoreactivity in the hippocampus and amygdala. In addition, spatial memory significantly improved due to the antidepressant treatment (Nelson et al., 2007). Another SSRI citalopram also altered Aβ production, by increasing the level of non-amyloidogenic APP by threefold (Pakaski et al., 2005). 7. Discussion It has become apparent that many players may contribute to the cognitive decline seen in MD. The overactivation of the HPA-axis in response to chronic stress, the subsequent downregulation in

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glucocorticoid receptors and hippocampal atrophy can be viewed as a putative mechanism. On the other hand, alterations in 5-HT receptors, albeit through polymorphisms in its promoter region, have also been implicated in significant limbic changes, leading to a broader spectrum of MD-related dysfunctions. The interaction between both systems is of vital importance, and may not be forgotten when researching this area. By back-and-forth stimulation of each other's receptors, detrimental alterations in one system can be exacerbated by the other. A similar pattern can be expected in AD, given the fact that both systems are also comprised in this illness. The overlap in pathology with respect to the HPA-axis dysfunction and reduced 5-HT receptor binding is quite apparent. Fig. 1. provides a simplified summary of the described interactions between the 5-HT pathway, the HPA-axis, MD and AD. MD is associated with a dysfunctional HPA-axis and serotonergic transmission, thereby attacking the integrity of the limbic system. As a consequence, the so-called reserve capacity of the brain may become compromised, which will manifest itself by cognitive and affective disturbances. This lack in reserve makes the brain less able to handle subsequent ADrelated neurodegeneration like the formation of neurofibrillary tangles and amyloid plaques (Katzman, 1993; Stern, 2002). Normally, the 5-HT system protects neurons from Aβ neurotoxicity, by favoring the release of non-amyloidogenic APP. However, MD-induced alterations in the serotonergic system lift this protection, thereby exacerbating AD neuropathology. Excessive levels of glucocorticoids aggravate Aβ and neurofibrillary tangle formation as well. Due to the presence of serotonergic receptors in the HPA-axis and the abundance of glucocorticoid receptor, mineralocorticoid receptor and

CRH receptors in the 5-HT system, a change in one system can have detrimental consequences for the other, leading to a vicious cycle. However, as can be seen in the figure, AD can also induce a higher vulnerability to develop MD, via the same mechanisms. Indeed, depression is a common feature among AD patients, with prevalence estimates ranging from 30–50% (Olin et al., 2002). The idea has been proposed that MD is not a risk factor for AD, but merely an early symptom (Geerlings et al., 2000; Swaab et al., 2005). It is thought that, especially in highly educated people, the cognitive changes are too subtle to measure, due to higher cognitive reserve, while the neurodegenerative nature of AD has already compromised the affective system enough to be noticed (Geerlings et al., 2000; Swaab et al., 2005). Another link between MD and AD could also be reflected in the change in BDNF concentrations. Both MD and AD patients exhibit decreased mRNA levels of BDNF in the hippocampus (Karege et al., 2005; Phillips et al., 1991). Since BDNF is a key molecule in regulating hippocampal plasticity, it is consequently of vital importance for hippocampal integrity and optimal functioning. Mouse models of AD, such as the J20 and PS1M146V knock-in model, both showed hippocampus-dependent learning and memory deficits, which could be correlated to the reduction in neurogenesis in the PS1M146V knock-in mouse model (Wang et al., 2004). In addition, the J20 mouse showed synapse loss and aberrant cell signaling which could be reversed by BDNF infusion (Nagahara et al., 2009). Improvement of cognitive and affective disabilities in MD after antidepressant treatment, has also been attributed to increases in BDNF (Duman and Monteggia, 2006). In this line, enhancing BDNF levels by administrating antidepressants could potentially prevent AD-related cognitive impairment. In conclusion, it can be postulated that the cognitive decline seen in depressed patients can, at least in part, be explained by alterations in the HPA-axis and serotonergic system. By rendering the brain more vulnerable for subsequent neurodegeneration and contributing to the formation of AD specific hallmarks, MD may be a risk factor for developing AD. Opinions on this matter are still divided, and only future research can provide us with new insights. Acknowlegdements The work of Dr. D. van den Hove and Dr. J. Prickaerts was partly funded by the European Commission Research Directorates, Research & Technological Development Project, 6th Framework Programme, LSHM-CT-2003-503474 (NEWMOOD). References

Fig. 1. Schematic and simplified overview of the interactions between the HPA-axis and the serotonergic system. Major depression leads to alterations (Δ) in both systems, which are highly interconnected. Abnormal HPA-axis function results in an excessive release of glucocorticoids (GCs) which can alter mineralocorticoid, glucocorticoid and 5-HT receptor function and induce structural changes in the limbic system thus resulting in emotional and cognitive dysfunction. This renders the limbic system more vulnerable for neurodegeneration caused by Alzheimer's disease and further deteriorates emotional and cognitive function. In addition both the 5-HT system and the glucocorticoids are able to influence production of amyloid-β and neurofibrillary tangles. Abbreviations: 5-HT: serotonin; Aβ: Amyloid-β; CRH: corticotrophin-releasing hormone; GCs: glucocorticoids; GR: glucocorticoid receptor; HPA: hypothalamuspituitary-adrenal; MR: mineralocorticoid receptor; NFT: neurofibrillary tangles.

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