New insights into brain BDNF function in normal aging and Alzheimer disease

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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v

Review

New insights into brain BDNF function in normal aging and Alzheimer disease Lucia Tapia-Arancibia a,b,c,⁎, Esteban Aliaga d , Michelle Silhol a,b,c , Sandor Arancibia a,b,c a

Inserm, U710, Montpellier, F-34095 France Univ Montpellier 2, Montpellier, F-34095 France c EPHE, Paris, F-75007 France d Centro de Neurobiología y Plasticidad del Desarrollo, Departamento de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Gran Bretaña 1111, Playa Ancha, Valparaíso, Chile b

A R T I C LE I N FO

AB S T R A C T

Article history:

The decline observed during aging involves multiple factors that influence several systems.

Accepted 30 July 2008

It is the case for learning and memory processes which are severely reduced with aging. It is

Available online 3 August 2008

admitted that these cognitive effects result from impaired neuronal plasticity, which is altered in normal aging but mainly in Alzheimer disease. Neurotrophins and their receptors,

Keywords:

notably BDNF, are expressed in brain areas exhibiting a high degree of plasticity (i.e. the

Aging

hippocampus, cerebral cortex) and are considered as genuine molecular mediators of

BDNF

functional and morphological synaptic plasticity. Modification of BDNF and/or the

ProBDNF

expression of its receptors (TrkB.FL, TrkB.T1 and TrkB.T2) have been described during

TrkB receptor

normal aging and Alzheimer disease. Interestingly, recent findings show that some

β-amyloid peptide

physiologic or pathologic age-associated changes in the central nervous system could be

Alzheimer disease

offset by administration of exogenous BDNF and/or by stimulating its receptor expression. These molecules may thus represent a physiological reserve which could determine physiological or pathological aging. These data suggest that boosting the expression or activity of these endogenous protective systems may be a promising therapeutic alternative to enhance healthy aging. © 2008 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . BDNF and neuronal plasticity . . . . . . . . . . . . . . . . . . BDNF gene and its receptors . . . . . . . . . . . . . . . . . . Distribution of BDNF and its receptors in the CNS . . . . . . BDNF system during normal aging . . . . . . . . . . . . . . . BDNF and Alzheimer disease . . . . . . . . . . . . . . . . . . Protective effect of BDNF against β-amyloid-induced toxicity

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⁎ Corresponding author. Inserm, U710, Univ Montpellier 2, cc 105, Place Eugène Bataillon, 34095 Montpellier, France. Fax: +33 467 14 33 86. ^ E-mail address: [email protected] (L. Tapia-Arancibia). 0165-0173/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2008.07.007

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8. Conclusion and prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212

1.

Introduction

Aging is a multifactorial process determined by genetic and epigenetic factors resulting in a broad functional decline including endocrine, immunological and cognitive functions. Thus, most aging individuals show gradual impairment of cognitive capabilities which are associated with hippocampus or cortical alterations, two brain regions involved in learning and memory processes. Diagnostic criteria of ageassociated memory impairment in humans were proposed by Crook et al. (1986). Nevertheless, changes in memory with age can be variable between individuals and all types of memory are not affected equally. In general, optimal cognitive functions are linked to efficient neuronal plasticity. The plasticity concept has highly evolved from the pioneer studies of Hebb (1949). Nowadays, some clever definitions have been proposed, notably that of Thoenen (1995) who stated that plasticity “is the capacity of neurons or glial cells to improve or to depress the synaptic efficacy through biochemical or morphological changes which evolve in a dynamical fashion”. This property is markedly decreased with aging and in pathological disorders such as Alzheimer disease (AD). There is accumulating evidence that neurotrophins are important molecular mediators of structural and functional plasticity (McAllister et al., 1999; Schinder and Poo, 2000; Thoenen, 2000; Lu et al., 2004; Arancio and Chao, 2007; Lynch et al., 2007; Tanaka et al., 2008) and also protect neurons against different kinds of brain insult (Lindvall et al., 1994; Tapia-Arancibia et al., 2004). One of these neurotrophins, i.e. BDNF and its receptors TrkB, is highly expressed in brain areas exhibiting a high degree of plasticity (i.e. the hippocampus, hypothalamus and cortex), regulates synaptic transmission, and in turn their expression is regulated by neuronal activity (Tapia-Arancibia et al., 2004). New evidence discussed in this article suggests that some types of learning training can also stimulate not only BDNF levels but the whole BDNF metabolism as well as TrkB receptor expression in aged rats. Besides, exogenous administration of BDNF can counteract the in vitro and in vivo neurotoxic effects of β-amyloids, which are well known pathological agents in AD.

2.

BDNF and neuronal plasticity

Two models of synaptic plasticity have been particularly studied: long-term potentiation (LTP) and long-term depression (LTD). The LTP concept considered as a substrate for memory (Lynch et al., 2007) was introduced by Bliss and Lomo in the early 1970s on the basis of studies on the hippocampus (Bliss and Lomo, 1973). They found that the efficacy of synaptic transmission, as measured by the size of the post-synaptic field potentials, was potentiated for several hours following a short, high frequency volley of stimuli. LTP is synaptic specific, rapidly induced and persistent which is

in keeping with the great capacity, rapid acquisition and stability of memory. By contrast, LTD is induced by lowfrequency stimulation and both LTP and LTD involve postsynaptic phosphorylation processes and glutamate receptor trafficking (Malenka, 2003). Neurotrophins are critical molecules that support the development, differentiation, maintenance and plasticity of brain function throughout life (Thoenen, 1995; Lewin and Barde, 1996). Among these molecules, brain-derived neurotrophic factor (BDNF) is involved in translating the activity signal into synaptic plasticity changes (McAllister et al., 1999). Recent data from Tanaka et al. (2008) shed lights on this crucial point that is how functional changes are transformed into structural changes. Dendritic spines, tiny structural elements that form synapses with other neurons, are the site where occur the structural changes influencing both neuronal activity and function. These authors showed that BDNF is necessary and sufficient to induce long-lasting structural changes at dendritic spines and that their enlargement could be blocked by inhibiting protein synthesis. In addition, intrahippocampal administration of BDNF affects short-term behavioral plasticity in adults rats (Cirulli et al., 2004). Thus; it seems that BDNF is required for some forms of hippocampus-mediated learning, probably through structural changes. In fact, induction of LTP in the hippocampus, rapidly and selectively increases BDNF mRNA levels (Patterson et al., 1992; Castren et al., 1993). In contrast, LTP is impaired in mice lacking the BDNF gene (Korte et al., 1995, 1996). Inversely, BDNF treatment of hippocampal slices dissected from BDNF knockout mice completely reverses deficits in LTP and significantly improves deficits in basal synaptic transmission at the Schaffer collateral-CA1 synapse (Patterson et al., 1996). Learning training, and short- or long-term memory formation induce BDNF mRNA up-regulation in the hippocampus (Hall et al., 2000; Alonso et al., 2002; Mizuno et al., 2003; Yamada and Nabeshima, 2003) while deprivation of endogenous BDNF results in impairment of special learning and memory in adult rats (Mu et al., 1999). In addition, forebrain-restricted BDNF mutant mice (Emx-BDNFKO) presented dramatic spatial learning deficits (Gorski et al., 2003a). These mutants, at 2month-old, had no differences in skeletal growth and body weight compared to wild type, and presented no abnormalities in tests for ataxia, anxiety or acoustic startle response (Gorski et al., 2003a,b). Although these mice exhibited a relative normal cytoarchitecture, they showed cortical dendritic retraction (Gorski et al., 2003b) and profound spatial learning deficits. In this model BDNF function seems to be more important in the maintenance of circuitry than in the initial development. Nevertheless, these alterations were less severe than impairments exhibited by forebrain-specific TrkB mutant mice (Minichiello et al., 1999). Formation of social recognition memory also increases BDNF and trkB expression in cortical and limbic regions in lambs (Broad et al. 2002). Visual input blockade resulted in down-regulation of BDNF

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mRNA in the rat visual cortex. In contrast, re-exposing animals to light after a period of darkness was found to reverse this change (Castren et al., 1992). BDNF mRNA is also up-regulated in the inferior temporal cortex during declarative memory formation in monkeys (Tokuyama et al., 2000) or in the rat hippocampus during contextual fear learning (Hall et al., 2000). On the contrary, LTD induction in rat visual cortex was prevented by BDNF pre-treatment (Akaneya et al., 1996). It has been reported that theta burst stimulation (Lin et al., 2005) and NMDA receptor stimulation (Kramàr et al., 2006) induced LTP and caused a rapid polymerization of actin in dendritic spines of hippocampus. Because BDNF induces late-phase LTP (Bramham, 2007; Zhou et al., 2008) and its expression is positively regulated by glutamate, BDNF may be released after these stimuli (Aicardi et al., 2004) and take part in LTP consolidation process. Accordingly, the BDNF scavenger (TrkB-Fc) completely blocked increases in spine F-actin produced by suprathreshold levels of both theta stimulation and LTP consolidation when applied 1– 2 min after theta trains (Rex et al., 2007). This data clearly indicate BDNF involvement in LTP-related cytoskeletal changes and memory storage (Soulè et al., 2006) in adult hippocampus. The efficacy of synaptic transmission can be modulated over a broad spectrum of temporal scales, ranging from synaptic modulation observed in seconds or minutes to alterations that persist for many hours (LTP in the hippocampus or LTD in the cerebellum) (Kovalchuk et al., 2004; McAllister et al., 1999), to days or years, as is the case in post-traumatic stress disorders (PTSD) (Sapolsky, 2000). BDNF at a low nanomolar range excited neurons in the hippocampus, cortex and cerebellum as rapidly (less than 10 ms) as the classic excitatory neurotransmitter glutamate (Kafitz et al., 1999). This BDNF-induced depolarization resulted from the activation of a sodium channel, more precisely Nav1.9 channels provided that they are expressed together with TrkB (Blum et al., 2002). In addition, BDNF is anterograde transported to nerve terminals (Zhou and Rush, 1996; Altar and Di Stefano, 1998) to act at post-synaptic levels (Levine et al., 1995; Suen et al., 1997; Kafitz et al., 1999) and it is secreted in an activity-dependent manner (Goodman et al., 1996; Pugh et al., 2006) inducing depolarizing effects (Kovalchuk et al., 2004). All these features assign to BDNF properties similar to conventional neurotransmitters. Besides, in cultured primary neurons and neuronal cell lines, BDNF is released through a regulated secretory pathway (Goodman et al., 1996) depending on extracellular calcium (Griesbeck et al., 1999). BDNF can also act as a neuromodulator affecting the presynaptic release of neurotransmitters in central neurons (Berninger and Poo, 1996; Jovanovic et al., 2000; Poo, 2001; Carvalho et al., 2008) and in nociceptive pathways (Pezet et al., 2002; Merighi et al., 2008). BDNF may exert rapid effects on both excitatory and inhibitory synaptic neurotransmission by changing the properties of post-synaptic ionotropic receptors after protein phosphorylation (Levine et al., 1995; Jovanovic et al., 2004; Rose et al., 2004). Finally, BDNF is co-stored in individual dense-core vesicles with some neuropeptide transmitters in a constant stechio-

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metric ratio (Salio et al., 2007) providing structural bases in favor of a BDNF neurotransmitter/neuromodulator function. Since BDNF is anterograde or retrograde transported an interesting point to be understood is how neurons choose to engage in these signaling and what factors determine this decision. Another plastic process by which adult brain may optimize its performances is the neurogenesis that occur essentially in the dentate gyrus and olfactory bulb (Lledo et al., 2006; Morgenstern et al., 2008; Pinnock and Herbert, 2008; Toni et al., 2008). Interestingly, there is a close correlation between factors or physiological situations (i.e. aging, stress, food deprivation, physical exercise, etc) that alter BDNF expression and those modifying neurogenesis in adult rats (Tapia-Arancibia et al., 2004). For example, living in an enriched environment enhances the number of newly generated cells in the hippocampus (Nilsson et al., 1999; Brown et al., 2003) and also the expression of BDNF mRNA (Falkenberg et al., 1992; Ickes et al., 2000). Learning increases adult neurogenesis (Gould et al., 1999; Gould and Gross, 2002), BDNF mRNA expression (Korte et al., 1995, 1996; Hall et al., 2000; Kovalchuk et al., 2002; Mizuno et al., 2003; Yamada and Nabeshima, 2003), BDNF, proBDNF and TrkB.FL content (Silhol et al., 2007b) in the hippocampus. Dietary restriction increases the number of newly generated neural cells and induces BDNF expression in the dentate gyrus (Lee et al., 2000, 2002; Gomez-Pinilla, 2008). Physical exercise, in the form of running but not swimming (van Praag et al., 1999; Brown et al., 2003), enhances cell proliferation and BDNF mRNA expression in the dentate gyrus (Neeper et al., 1996; Oliff et al., 1998; Russo-Neustadt et al., 2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus (Malberg et al., 2000) and also BDNF mRNA levels (Altar, 1999). Glucocorticoids inhibit cell proliferation in the dentate gyrus (Gould et al., 1992, 1998; Pinnock and Herbert, 2008) and down-regulate BDNF mRNA expression (Smith et al., 1995). By contrast, estrogens increase cell proliferation in the dentate gyrus (Tanapat et al. 1999; Ormerod and Galea, 2001) and also BDNF mRNA levels (Solum and Handa, 2002; Sohrabji and Lewis, 2006). Moreover, infusion of BDNF into the lateral ventricle of the adult rat enhanced cell proliferation in the parenchyma of the striatum, septum, thalamus, and hypothalamus (Pencea et al., 2001). Although these studies did not demonstrate if BDNF directly mediated these effects, they report striking correlations allowing envisaging a cause–effect relationship between BDNF levels and neurogenesis. Taken together, these data show that BDNF has important roles in the plasticity of several regions of the central nervous system (CNS) in adulthood and in aging. This property depends on a number of functional and morphological changes ranging from protein phosphorylation and cytoskeletal reorganization of dendritic spines to generation of new neurons. In hippocampal neurons cyclic AMP controls specifically BDNF-induced TrkB phosphorylation and dendritic spine formation by modulating the signaling and trafficking of TrkB (Ji et al., 2005). Therefore an exciting new challenge is to gain insight into the link between TrkB receptor signaling and cytoskeleton changes which can explain modifications of dendritic spines morphology.

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3.

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BDNF gene and its receptors

The rodent BDNF gene was initially described by Timmusk et al. (1993) and consisted of four 5′-exons (I–IV) linked to separate promoters and one 3′-exon (V) encoding the mature BDNF protein. More recently, Pruunsild et al. (2007) and Aid et al. (2007) have identified new splice variants in human and rodents, respectively, showing that at least 11 different BDNF transcripts can be generated from the mammalian rodent BDNF gene by alternative splicing (Fig. 1). The activation of different BDNF promoters is region-specific and depends on the type of stimulus (Metsis et al., 1993; Timmusk et al., 1993; Bishop et al., 1994; Kokaia et al., 1994; Lauterborn et al., 1998; Givalois et al., 2001; Aliaga et al., 2002). The multiplicity of functions in which BDNF is involved seems to be correlated with the complexity of its gene and its exquisite regulation. A relevant observation is that BDNF mRNAs are polyadelynated at two alternative sites, leading to distinct populations of mRNAs, either with a short 3′ unstranslated region (UTR) or

Fig. 1 – Schematic representation of the rodent BDNF gene according to Timmusk et al. (1993) (top) and Aid et al. (2007) (middle). Exons are represented as boxes and introns as lines. The 22 possible transcripts from the gene described by Aid et al., are shown below the gene scheme, with lines indicating alternative splicing sites. On the bottom scheme is shown the human BDNF gene recently reported by Pruunsild et al. (2007).

with a long 3′ UTR (Ghosh et al., 1994; Timmusk et al., 1993) resulting in 22 different BDNF transcripts in rodents, all of them encoding the same BDNF molecule (Fig. 1). A very recent report provided new insights on this peculiar diversity of BDNF mRNAs (An et al., 2008). This study indicated that the short 3′UTR BDNF mRNAs were confined in the neuronal soma and the long 3′UTR BDNF mRNAs were localized in dendrites. This new information confers an important physiological signification to the existence of short and long 3′UTR forms of BDNF mRNA as mice lacking the long 3′UTR mRNA presented altered late-phase LTP and unfinished synaptic pruning. Indeed, translation of the long forms of BDNF mRNA in dendrites may control synaptic plasticity locally whereas translation of the short forms in the soma may participate in neuronal survival and maintenance or in the synthesis of neurotransmitter or receptors regulating neuronal activity. BDNF could serve as an associative messenger for the consolidation of synaptic plasticity inducing dendritic protein synthesis activation (Aakalu et al., 2001) and structural plasticity of single dendrites spines (Tanaka et al., 2008). Interestingly, dendritic localization and activity-dependent dendritic targeting of mRNAs encoding BDNF and its TrkB receptor have been described in hippocampal neurons in vitro (Tongiorgi et al., 1997) and in vivo (Simonato et al., 2002). Moreover, induction of dendritic targeting of BDNF mRNA in hippocampal neurons has been observed, for example, in plastic changes underlying epileptogenesis (Tongiorgi et al. 2004). The targeting of certain mRNAs to specific subcellular compartments, particularly to dendrites, is an important feature linked to synaptic plasticity, especially since the functional translation machinery is present in the dendritic compartment to allow local protein synthesis (Steward, 1994; Steward et al., 1998). This issue is particularly relevant because some BDNF transcripts are regulated as early genes in central neurons following electric stimulation (Lauterborn et al., 1996), glutamate treatment or NMDA receptor activation (Hughes et al., 1993; Marmigère et al., 2001) thus allowing rapid physiological responses. Only a select group of mRNAs, principally those encoding plasticity-related molecules, undergo this type of post-transcriptional regulation (Steward et al., 1998; Kuhl and Skehel, 1998). Nevertheless, mRNA localization in dendrites differs considerably between neuronal types both in vivo and in vitro and under different physiological conditions (Steward, 1997). Certain dendritic mRNAs (i.e. αCAMKII and Arc) are distributed throughout the processes, while others are concentrated in proximal dendrites (e.g. MAP2) (Steward et al., 1996). Local protein synthesis of plasticity-related molecules may be crucial for some aspects of neuronal development (Richter and Lorenz, 2002) and synaptic efficiency (Schuman, 1999; Sutton and Schuman, 2006). Transcript-specific localization of BDNF mRNA has been documented in dendritic cortical neurons in vivo (Pattabiraman et al., 2005) and in vitro (Aliaga et al., personal observations) (Fig. 2). mRNA targeting toward the dendritic compartment could represent a potential point of regulation by factors impairing synaptic plasticity (i.e. the β-amyloid peptides or the hyperphosphorylated tau protein). BDNF exerts its multiple biological actions through TrkB receptors generated by alternative splicing of trkB mRNA. Three different TrkB receptors with different signaling

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Fig. 2 – Neuronal localization of exon-specific transcripts in cultured cortical neurons. BDNF transcripts were detected by DIG-labeled in situ hybridization. Strong hybridization label for exons II (II Aid), III (IV Aid) and IV (VI Aid) mRNA signals was found. Note that exon I is essentially localized in the soma; exons II and III in the soma and proximal dendrites; and exon IV in the soma, proximal and distal dendrites. Scale bar = 20 µm.

capabilities have been described so far (Klein et al., 1989, 1990; Soppet et al., 1991): the full-length catalytic receptor (TrkB.FL) and two truncated isoforms (TrkB.T1 and TrkB.T2). The truncated forms lack intracellular tyrosine kinase activity (Klein et al., 1990; Middlemas et al., 1991), although they trigger transduction signals (Baxter et al., 1997; Rose et al., 2003) resulting in different biological responses (Yacoubian and Lo, 2000). TrkB.FL is a transmembrane tyrosine kinase receptor with a conserved intracellular domain that mediates several well-characterized signaling pathways, including those controlled by Ras, the Cdc42/Rac/RhoG protein family, MAPK, PI3K and PLC-γ (Chao, 2003; Kaplan and Miller, 2000; Patapoutian and Reichardt, 2001). BDNF and TrkB mRNA expression vary as a function of development, age and cognitive performance (Croll et al., 1998; Fryer et al., 1996; Ivanova and Beyer, 2001; Silhol et al., 2005). TrkB.FL protein levels increased during development (Fryer et al., 1996). Conversely, we (Table 1) and others (Croll et al., 1998) have reported a reduction in TrkB.FL protein in the hippocampus of aged rats. We recently reported that spatial memory training strongly increased precursor BDNF metabolism in young and aged rat hippocampus and that this task increased

Table 1 – Hippocampal BDNF and TrkB proteins in aged (22–24-month-old) male rats compared to young rats (2-month-old) in different rat strains Strain

BDNF aged vs. young

Sprague No Dawley change No change Increase Wistar

Increase

Fisher 344 Lou/C

Decrease No change

Assay

TrkB.FL aged vs. young

References

Western

Reduction Silhol et al. (2005) ELISA n.d. Croll et al. (1998) ELISA n.d. Katoh-Semba et al. (1998) Western Reduction Silhol et al. (2007b) Immunoreactivity n.d. Hattiangady et al. (2005) Western Reduction Silhol et al. (2007a)

Abbreviations: ELISA: two-site enzyme-immunoassay system, n.d. = not determined.

TrkB.FL content in aged rats (Silhol et al., 2007b). Croll et al. (1998) previously documented that in aged rats, a decrease in trkB mRNA in the pons predicted impaired memory performance. In addition, conditional mutant mice in which the ablation of trkB is restricted to the forebrain during post-natal development displayed later impaired learning and hippocampal LTP which were associated with altered spine morphology (von Bohlen Und Halbach and Minichiello, 2006). Taken together these data indicate that a decrease in these molecules (ligand and receptor) importantly located in dendrites, could participate at least partially in memory impairments occurring in aged animals. Besides the complexity of its gene the biological actions of BDNF are also intricate. In fact, pro- and mature BDNF activate different receptors and intracellular pathways, potentially leading to either neuronal death or survival. Thus, BDNF binds to the unselective low-affinity p75NGFR receptor, a member of the tumor necrosis factor receptor (TNF) superfamily (Bothwell, 1995; Kaplan and Miller, 2000). p75NGFR lacks intrinsic catalytic activity, and signals through a series of protein–protein interactions mediated by its intracellular juxtamembrane and death domains (Hempstead, 2002; Lee et al., 2001). The activation of p75NGFR receptor can cause apoptosis in a variety of systems (Barrett, 2000). When coexpressed with the appropriate Trk receptor, p75NGFR increases neurotrophin-binding affinity and can contribute to ligand discrimination by different Trk family members contributing to classic neurotrophin biological effects (Bibel et al., 1999; Hempstead, 2002). Nevertheless, p75NGFR may also bind, with high affinity, proneurotrophins which can also be secreted as propeptides (i.e. proBDNF, Mowla et al., 2001). ProBDNF induces neuronal apoptosis (Lee et al., 2001) via activation of a receptor complex of p75NGFR and sortilin (Teng et al., 2005). In contrast, these proneurotrophins minimally bind to Trk receptors. BDNF and proBDNF have been reported to have opposite functional effects by regulating LTP or LTD in hippocampal slices. In fact, activation of p75NTR by proBDNF would facilitate NMDA receptor-dependent LTD in the hippocampus, effect that would be mediated through an upregulation of NR2B, an NMDA subtype uniquely involved in LTD (Woo et al., 2005). This study demonstrated that the application of proBDNF to hippocampal slices enhanced LTD in the CA1 neurons. This potentiating effect is likely postsynaptic, since p75NTR was colocalized with PSD95 (a marker

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for post-synaptic density often localized in dendritic spines). It was absent in p75NTR−/− mice or after application of a p75NTRblocking antibody in wild-type mice. Nevertheless, Matsumoto et al. (2008) recently documented that LTD is unaffected in slices prepared from cBDNF KO animals. This study showed that BDNF, but not proBDNF, was accumulated and then secreted upon neuronal stimulation indicating that proBDNF is a transient biosynthetic intermediate that undergoes intracellular processing. These apparent discrepancies must be examined with caution, since in the former report exogenous cleavage-resistant proBDNF was added to induce LTD. Nevertheless, in physiological conditions, neurons probably have no high amounts of available extracellular proBDNF because the endogenous proBDNF is rapidly converted to BDNF as demonstrated in Matsumoto et al., report. (2008). In any case, the balance between cell survival and cell death might depend upon the proportions of mature and proneurotrophin available to cells expressing Trk and p75NGFR receptors. Regulation of the expression or activation of specific proteases in particular physiological or pathological conditions (stress, aging, neurodegeneration, inflammation or injury) could therefore be extremely important in determining pro- or antiapoptotic cellular responses (Chao and Bothwell, 2002; Ibañez, 2002).

4. CNS

Distribution of BDNF and its receptors in the

In adult rat brain, BDNF mRNA is expressed in the hippocampus, septum, hypothalamus, cortex and in adrenergic brain stem nuclei (Castren et al., 1995; Katoh-Semba et al., 1997). BDNF immunoreactivity is also widespread in adult rat brain, including cerebral cortex, hippocampus, basal forebrain, striatum, hypothalamus, brainstem and cerebellum (Kawamoto et al., 1996) where it was visualized in soma, dendrites and fibers. In addition, in rat hippocampus, amygdala and cingulated, parietal and entorhinal cortex BDNF immunoreactivity has also been observed in soma nuclei (Wetmore et al., 1991). This particular BDNF protein location suggests that this neurotrophin may enter the nucleus of neurons to directly influence transcription in vivo. In general, there is a substantial overlap between BDNF mRNA and protein expression, but there are discrete anatomical regions where there is discordance. It has also been reported that BDNF mRNA levels and protein levels are not correlated in rats after antidepressant treatments and lithium (Jacobsen and Mork, 2004) or in aged rats (Silhol et al., 2005, 2007b). There are several explanations for this mismatch: mRNA levels in basal conditions may be too low to be detected by in situ hybridization techniques; the amount of protein may also be too low to be detected by immunohistochemistry; the protein may be released or transported (anterograde or retrograde); the protein may be localized in a subcellular region distinct from mRNA. Alternatively, the protein may be present in a prepro or unfolded state which prevents recognition by the antibody. ELISA assay recognizes all BDNFcontaining molecules and not only the active molecule as discussed elsewhere. Finally, transcription and translation are

differentially regulated processes. For example, comparative studies of BDNF mRNA and protein at the cellular level have revealed immunostained-labeled neurons in striatum, whereas the mRNA is not found there in basal conditions, but only after seizures (Schmidh-Kastner et al., 1996). These findings have given raise to the hypothesis that BDNF could be a target-derived factor for dopaminergic neurons of substantia nigra. In some discrete regions of the hippocampus formation, the cellular localization of immunoreactivity also differs from the BDNF mRNA distribution. Moderate immunoreactivity is noted in neuronal soma and fibers of granule cell layers (Schmidh-Kastner et al., 1996). Little or no BDNF immunoreactivity was detected in granule cell soma of the dentate gyrus and pyramidal neurons despite the high BDNF mRNA expression (Yan et al., 1997). In contrast, in the hilus of the dentate gyrus and molecular layer many fibers are stained whereas the CA2 region presents strong immunoreactivity (Kawamoto et al., 1996). It should also be kept in mind that when no BDNF peptide is detected in a particular region, the assay or antibody used might not be sensitive enough to measure what is there “non-detectable” should not be equated with “absent”. In addition, since neurotrophins are rapidly transported, it is likely that BDNF concentrations in soma do not accumulate over time. Immunocytochemical localization of TrkB in the CNS has shown staining in cell bodies, axons and dendrites (Fryer et al., 1996). Distinct and widespread staining was described in many structures i.e. cerebral cortex, olfactory bulb, hippocampus, thalamus and hypothalamus, dentate gyrus, striatum, septum and basal ganglia, substantia nigra, cerebellum, brainstem and spinal motor neurons, and brainstem sensory nuclei (Yan et al., 1997, Drake et al., 1999). trkB mRNA was also found in these regions, notably in frontal cortex, cingulated cortex, entorhinal cortex, hippocampus or hypothalamus, where its expression is developmentally regulated (Fryer et al., 1996). In the hippocampus, strong staining was detected in the pyramidal layers of CA1-CA4 regions, in the granular layer of the dentate gyrus, in dentate granular neuron cell bodies and in their dendrites (Yan et al., 1997). Interestingly, trkB mRNA, but not trkA or trkC mRNAs are found in neuronal dendrites (Tongiorgi et al., 1997, 2000) and it is necessary for post-natal maintenance of hippocampal spines (von Bohlen und Halbach et al., 2008). Coexpression of BDNF and its receptors has been demonstrated in individual hippocampal and cortical neurons (Kokaia et al., 1994) thus suggesting that autocrine or paracrine mechanisms account for the general modality of BDNF action in the CNS. Nevertheless, as it is dendritically released (Arancibia et al., 2007) it can also diffuse to distant brain targets to bring on neuronal network organization (Ludwig and Leng, 2006).

5.

BDNF system during normal aging

Plasticity is markedly reduced with aging (Burke and Barnes, 2006). During normal aging in spite of minor changes in hippocampal morphology (Barnes, 1994) impairments in LTP have been reported (Pang and Lu, 2004; Rex et al., 2005). The reader will find valuable information on the effects of aging on

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LTP and cognition in very informative reviews on this topic (Rosenzweig and Barnes, 2003; Lynch et al., 2006). Spatial learning can become impaired without evidence of neuron loss. These changes seem to be correlated with BDNF decreases (discussed below) or with its associated transduction mechanisms (Gooney et al., 2004). Indeed, BDNF-induced LTP in dentate gyrus is impaired with age probably due to age-related changes in receptor function. Rex et al. (2006) reported that plasticity changes may be reverted by endogenous induction of BDNF by an ampakine. Acute administration of ampakines positively modulate AMPA receptors in brain and restores LTP to the basal dendrites of middle-aged slices (Rex et al., 2006) and improves age-associated memory impairments in rats (Granger et al., 1996). Age-related changes including modifications in hippocampal plasticity and decreased neurogenesis in the dentate gyrus and sub-ventricular zone (Drapeau and Nora Abrous, in press) can also be reversed under environmental influences (Mora et al., 2007) which simultaneously increase BDNF levels. In aged humans, several reports have described changes in these plasticity-related molecules at central or peripheral levels (Table 2). For example BDNF plasma levels have been reported to be significantly decreased in aged subjects (Lommatzsch et al., 2005). More recently Ziegenhorn et al. (2007) using a large cohort of healthy and diseased individuals confirmed these data and showed that there was a negative correlation between serum BDNF levels and age in healthy old adults (N70-year-old; n = 259). However, when data from old healthy and disease (depressed and demented) subjects were pooled, changes were no significant. BDNF produced in cells from the central nervous system is no the sole source of plasma BDNF as vascular endothelial cells and smooth muscle cells also synthesize BDNF (Donovan et al., 1995; Lommatzsch et al., 1999; Nakahashi et al., 2000). Human platelets also contain huge amounts of BDNF protein which largely contribute to serum BDNF levels (Radka et al., 1996). It has been suggested that they could participate to the regulation of the homeostasis by storing BDNF for later release in times of increased central nervous system demand (Fujimura et al., 2002). In normal aged humans, an absence of neuronal loss has been shown in the zone of CA1 pyramidal neurons of the hippocampus, whereas they are severely damaged in Alzheimer disease (West, 1993). The same observation has been reported in 2-year-old rats that are equivalent to a human age group of 65. In addition, regionally specific changes in hippocampal transmission have been reported in aged rats (Barnes, 1994). A loss of synapses in the

rat dentate gyrus as a function of normal aging (Geinisman et al., 1992) and age-related decline in spatial memory (Geinisman et al., 1986), also correlated with a decrease in BDNF mRNA expression (Schaaf et al., 2001) have been documented. Although neuronal death in neurodegenerative diseases is definitely an important factor in the decline of cognitive functions, the loss of dendrite spines in the absence of cell death probably contribute to impaired brain function in these diseases and also, in to a lesser degree, in normal aging. Since BDNF (Schuman et al., 2006) and trkB mRNAs (Tongiorgi et al., 1997) are localized within dendritic spines and since the dendritic spine density is significantly reduced in aged individuals (Hof and Morrison, 2004), there seems to be a clear link between BDNF and trkB mRNA expressions and impaired synaptic connexions with aging. Changes in spine shape and its turnover may modify existing synaptic connections and impair neuronal connectivity as discussed above. In middle-aged rats (8–10-month-old) BDNF induction can restore LTP impairment (Rex et al., 2005, 2006) and BDNF infusion normalizes the content of several peptides in aged rat cortex and hippocampus (Croll et al., 1999). BDNF is also necessary for maintenance of noradrenergic (Matsunaga et al., 2004) and serotonergic (Luellen et al., 2007) innervations in the aged rat brain. However, we and others have reported that BDNF and TrkB expressions vary in aged rat depending on the strain (Table 1). Katoh-Semba et al. (1998) documented that in male Sprague Dawley rats BDNF content was increased in the hippocampus and decreased in the cerebral cortex, hypothalamus and striatum with aging. In the same strain, we found a slight but significant decrease in BDNF content in the hippocampus and hypothalamus of aged rats also using ELISA but with other antibody and a different result expression (Silhol et al., 2005). Nevertheless, in the same study, when we analyzed the hippocampus by Western blot, no significant modifications in BDNF content were observed with aging, in keeping with data from Croll et al. (1998). Interestingly, we noticed a significant reduction in TrkB.FL and TrkB.T2 receptors in the hippocampus of aged rats, while TrkB.T1 receptors were unchanged (Silhol et al., 2005). It should be kept in mind that when analyzing BDNF content it is essential to consider the analysis method used for measurements since BDNF levels determined by ELISA assay detect BDNF, proBDNF and all BDNF-containing molecules. By contrast, Western blot analysis performed with the appropriate molecular weight markers discriminates between the BDNF content, corresponding to the active (trophic or protective) molecule (MW

Table 2 – Changes in BDNF and Trk receptors in humans Conditions Aged vs. young Aged vs. young Infant, young adult, elderly, adult Infant, young adult, elderly

Assay

BDNF and/or related molecules

Structure

Reference

ELISA ELISA ISH

↓BDNF ↓BDNF BDNF prenatal ages N adults

Serum Plasma Hippocampus

Ziegenhorn et al. (2007) Lommatzsch et al. (2005) Quartu et al. (1999)

Northern blot ISH

trkB.FL mRNA infant N young N elderly

Cortical area prefrontal cortex

Romanczyk et al. (2002)

Abbreviations: ISH, in situ hybridization; ELISA, two-site enzyme-immunoassay system.

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14 kDa) and the proBDNF content (36 kDa) (Fayard et al., 2005; Silhol et al., 2007b). ELISA results thus require careful confirmation with Western blot or immunocytochemistry using very specific antibodies, especially since proBDNF may exert completely opposite physiologic effects than BDNF, as noted above (Teng et al., 2005). In male Fischer rats, it has been reported that BDNF declines as early as middle age in the dentate gyrus, CA1 and CA3 layers, with no further changes during ageing (Hattiangady et al., 2005). In male Wistar rats, we have shown that aged rats had significantly higher amounts of BDNF and proBDNF in the hippocampus, whereas the catalytic receptor TrkB.FL was decreased and TrkB.T1 was increased. Interestingly, the levels of these receptors were normalized to values similar to those measured in young males when rats underwent spatial memory training. Besides, training strongly increased precursor BDNF metabolism in young and aged rats, resulting in increased levels of proBDNF in young and aged rats, whereas in old rats the mature BDNF levels remained unchanged (Silhol et al., 2007b). We have also analyzed these molecules in Lou/C rats which are an inbred strain of Wistar origin. This strain is considered as an animal model of successful aging, presenting a longer life span than most of laboratory rat strains (Alliot et al., 2002). In male Lou/C rats, we observed that the BDNF content did not change with aging. By contrast, aged Lou/C rats presented lower proBDNF content and a weaker decrease in catalytic receptors (TrkB.FL) compared to aged Wistar rats. Conversely, TrkB.T1 receptors were unchanged in aged Lou/C rats (Silhol et al., 2007a). In the gerbil hippocampus, age-dependent reductions in BDNF immunoreactivity have been noted in the CA1 area and in the dentate gyrus correlated with neuronal loss and decreased memory (Hwang et al., 2006). In aged macaque monkeys, it has been reported that the BDNF gene expression strongly decreased in various cerebral subdivisions, i.e. the hippocampus. Taken together, these data indicate that BDNF and its receptors have an important role during aging. Data indicate that when the BDNF content is unchanged or increased, as occurs for example in the hippocampus of aged Sprague Dawley or Wistar rats, respectively, the catalytic receptors levels are decreased, thus certainly resulting in a weaker BDNF action. As in most of the studies, receptors have been detected by western blot or immunocytochemistry, a decrease of receptors is probably associated with biochemical modifications, i.e. glycation, carbonylation, etc that technically impede its recognition by the antibody and possibly by the ligand. Interestingly, we observed that a spatial learning task could normalize these receptors levels in aged Wistar rats (Silhol et al., 2007b). Data also suggest that activation of the BDNF system may enhance healthy aging and that its exogenous administration could potentially help to regenerate certain neuronal populations in some degenerative pathologies.

6.

BDNF and Alzheimer disease

Growing evidence suggest that a decrease in BDNF levels could be associated with AD pathogenesis (Fumagalli et al., 2006).

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by mild cognitive impairment at onset and deficits in multiple cortical functions in later stages. In the dementia stages, numerous senile plaques and neurofibrillary tangles are observed accompanied by deficits in axonal transport and neuronal loss. Indeed, the neuropathological hallmarks of this disease are essentially β-amyloid plaques and Tau/neurofibrillary tangles consisting of paired helical filaments of hyperphosphorylated tau. The senile plaques are essentially composed of amyloid β-peptide (Aβ), a 40–42 amino acid peptide fragment of the β-amyloid precursor (APP) (Glenner and Wong, 1984), but also of Aβ25–35 oligomers (Kubo et al., 2002; Gruden et al., 2007). Aβ accumulation can result in oxidative stress, inflammation, and neurotoxicity, all of which can initiate the pathogenic cascade, ultimately leading to apoptosis and deterioration of the neurotransmission systems (Yankner, 1996). The impossibility of early detection of neurological insults makes it difficult to understand the mechanism and chronology of events interfering with neuronal function before neurodegeneration. Murer et al. (1999) demonstrated in AD brains that neurons containing neurofibrillary tangles did not contain BDNFimmunoreactive material, whereas most intensely BDNFlabeled neurons were devoid of tangles. Besides, in the hippocampus of AD patients, high amounts of BDNF truncated receptors have been found in the senile plaques (Connor et al., 1996). AD patients also exhibit degeneration of serotonergic neurons which results in severe alteration of the serotonergic system in the central nervous system (Morgan et al., 1987). As serotonin and BDNF are two close and reciprocally regulated signals (Mattson et al., 2004) a BDNF alteration could also contribute to degenerative disorders through modifications of the serotonergic system. Alteration in the expression of these molecules certainly contributes to depression or the mood disorders observed in aged and AD individuals (Altar, 1999). In AD patients, it has been documented that BDNF expression (Phillips et al., 1991; Siegel and Chauhan, 2000) and TrkB.FLIR (Allen et al., 1991) are severely decreased in the hippocampus and some cortical areas, i.e. temporal and frontal cortex. Most of the studies on BDNF expression (Table 3) have been done in post-mortem brains of AD or aged patients showing reduced BDNF levels compared with healthy subjects (Connor et al., 1997; Fahnestock et al., 2002; Ferrer et al., 1999; Hock et al., 2000, Holsinger et al., 2000; Murray et al., 1994; Phillips et al., 1991). In contrast, Durany et al. (2000) reported a significant increase of BDNF content in hippocampus of AD patients. The precursor form of BDNF and mature BDNF (Peng et al., 2005; Michalski and Fahnestock, 2003) or its mRNA (Holsinger et al., 2000; Phillips et al., 1991) were also decreased in the parietal cortex and hippocampus, even in pre-clinical stages of AD. An interesting overview of neurotrophin content in post-mortem human and transgenic mouse models can be found in a recent report by Schulte-Herbruggen et al. (2008). The big problem with human post-mortem studies is the difficulties linked to post-mortem delay of sampling. Some studies indicate the post-mortem delay which can oscillate between 3 and 29 h (Durany et al., 2000) or up to 33 h (Allen et al., 1999) that seems an extremely long time to be sure of protein or mRNA integrity. In addition, it is extremely difficult to be sure that peptide decreases are specific because in

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Table 3 – Changes in BDNF and Trk receptors in AD humans Conditions

Assay

BDNF and/or related molecules

Structure

Post-mortem AD

Western blot

Parietal cortex

Peng et al. (2005)

Post-mortem AD

IHCC

Post-mortem AD Post-mortem AD Post-mortem AD

RT-PCR Western blot Western blot RT-PCR ELISA

Hippocampus Temporal cortex Parietal cortex

Connor et al., (1997)

Post-mortem AD

Post-mortem AD Post-mortem AD

ELISA ELISA

Post-mortem AD

ELISA

Post-mortem AD Post-mortem AD Post-mortem AD

ISH ISH ELISA ELISA

↓BDNF ↓proBDNF ↓BDNF ↓BDNF ↓BDNF mRNA ↓proBDNF ↓proBDNF ↓BDNF mRNA ↔BDNF ↓BDNF ↓BDNF ↔BDNF ↑BDNF ↓BDNF ↓BDNF ↔BDNF ↓BDNF ↔BDNF ↓BDNF mRNA ↓BDNF mRNA ↔BDNF ↑BDNF (early AD) ↓BDNF (late AD) ↓BDNF ↑trk mRNA ↑TrkA, ↑TrkB.FL and truncated receptors ↓TrkB ↔TrkB truncated ↓trkA mRNA ↓TrkA, ↓TrkC ↔TrkB

Post-mortem AD

ELISA ISH IHCC Western blot Western blot

Post-mortem AD Post-mortem AD

RT-PCR IHCC

Post-mortem AD

Parietal cortex Parietal cortex Frontal cortex Parietal cortex Hippocampus Cerebellum Hippocampus Frontal cortex Hippocampus Motor cortex Entorhinal cortex Dentate cortex Hippocampus Hippocampus Serum Serum, CSF Serum, CSF Serum Hippocampus

Frontal cortex and temporal cortex Parietal cortex Parietal cortex

Reference

Fahnestock et al. (2002) Michalski and Fahnestock (2003) Holsinger et al. (2000) Hock et al. (2000)

Durany et al. (2000) Ferrer et al. (1999) Narisawa-Saito et al. (1996)

Phillips et al. (1991) Murray et al. (1994) Ziegenhorn et al. (2007) Laske et al. (2006) Laske et al. (2007) Connor et al. (1996)

Allen et al. (1999) Hock et al. (1998) Savaskan et al. (2000)

Abbreviations: IHCC, immunocytochemistry; ISH, in situ hybridization; ELISA, two-site enzyme-immunoassay system; RT-PCR, reverse transcription polymerase chain reaction; CSF, cerebral spinal fluid.

neurodegenerative diseases a loss of cell density, dendritic spines, afferences, synapses, etc., may secondarily result in a large reduction of peptides and/or neurotransmitters. It would be essential to measure in parallel a non-changing control protein to express results related to this internal control. Decreased protein levels measured by ELISA and immunohistochemistry may represent a mixture of BDNF and proBDNF or BDNF-containing molecules as discussed above. BDNF serum concentration is other parameter which has been also analyzed in AD patients; it varies over the course of the disease and is correlated with the severity of dementia (Laske et al., 2007). In this study including males and females of around 70-year-old, it was reported that at early stages of AD, BDNF significantly increased vs. control groups whereas at more severe stages of AD, it decreased. Ziegenhorn et al. (2007) using a separate and bigger cohort of demented males or female individuals than that of the precedent report showed that BDNF serum levels were not significantly modified vs. healthy group. Finally, also using post-mortem tissue, CREB, a crucial BDNF signaling molecule, has been reported to be impaired in AD patients (Yamamoto-Sasaki et al., 1999). In vitro models have been extensively used to study βamyloid mechanisms involved in AD. Among these molecular mechanisms, it has been found that Aβ1–42 modulates TrkB

expression in the cellular surface in neuroblastoma cells (Olivieri et al., 2003). In cortical neurons, at sublethal concentrations, β-amyloid impairs the transduction path activated by BDNF (Ras/ERK; PI3-K/AKT) (Tong et al., 2001, 2004), the PKA/CREB pathway and LTP (Vitolo et al., 2002), as well as BDNF-induced arc expression (Wang et al., 2006a). In PC12 transfected cells, β-amyloid, at high concentrations, blocks nuclear translocation of P-CREB (Arvanitis et al., 2007). In human neuroblastoma cells, it has also been reported that oligomeric but not fibrilar Aβ1–42 decreases P-CREB and total BDNF mRNA (Garzon and Fahnestock, 2007). In rat cortical neurons, NIH-3T3 cells p75NTR expressing cells or melanocytes, it has been shown that β-amyloid (1–40) binds to the p75NTR neurotrophin receptor, inducing apoptosis (Yaar et al., 1997, 2002; Sotthibundhu et al., 2008). Amyloid β-peptide inhibits the late-phase of LTP which is dependent on local protein synthesis in the hippocampal dentate gyrus (Chen et al., 2002). In a similar paradigm, BDNF stimulates the local synthesis of proteins that are required for LTP induction (Kang and Schuman, 1996). More recently, Snyder et al. (2005) reported a potential pathway by which β-amyloid reduced glutamatergic transmission and NMDA receptor-dependent LTP. These authors showed that β-amyloid leads to internalization of NMDA receptors reducing their availability at synapses. Since BDNF

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expression is regulated by glutamate (Tapia-Arancibia et al., 2004) and in turn BDNF regulates glutamatergic neurotransmission (Li et al., 1998; Matsumoto et al., 2006) and traffic of NMDA receptors (Caldeira et al., 2007), alterations in this pathway can also contribute to explain synaptic dysfunction in AD pathology. Interestingly, BDNF also induces rapid in vitro dephosphorylation of tau protein in a neuronal cell line (P19) (Elliott et al., 2005). Tau isoforms have been proposed as appropriate markers of aging and neurodegenerative disorders (Hernandez et al., 2008) since there is a dramatic increase in the capacity of the tau protein when hyperphosphorylated to bind to microtubules. Changes in the solubility characteristics of these hyperphosphorylated proteins contribute to form different types of aggregates in some neurodegenerative disorders, such as in AD. In contrast to most of the data reported above in AD humans, in APP23 transgenic mice, a rodent AD model overexpressing the amyloid precursor protein, higher BDNF contents in frontal cortex than wild type have been noticed (Hellweg et al., 2006). These mice also presented age-dependent increases in cortical and striatal BDNF concentrations (Schulte-Herbruggen et al., 2008). Using the same model, Burbach et al. (2004) also reported an up-regulation of BDNF mRNA and protein correlated with the β-amyloid load. They observed a BDNF mRNA gradient surrounding the amyloid plaques in the cerebral cortex of aged transgenic mice. Immunocytochemistry analysis indicated that BDNF was present in glial cells and dystrophic boutons in the immediate plaque vicinity. Insofar as changes in BDNF in the immediate plaque vicinity are observed, the expression of BDNF by microglial and astroglial cells indicates an eventual link between BDNF and inflammatory and/or defensive processes as these cells participate in the clearance of amyloid peptides (Rogers et al., 2002). APP23 adult mice exhibited similar performances in the radial maze than wild-type mice but their performances were impaired in the complex maze, a test known to require a more preserved hippocampal function than the radial maze (Hellweg et al., 2006). Obviously, transgenic mice that show moderate neurodegeneration even at late stages cannot be compared with the severe neurodegeneration of AD patients presenting huge neuronal loss. In addition, in these studies BDNF content was generally determined by ELISA assay in homogenates of whole regions, so it cannot be excluded alterations in discrete areas. Overall, these data show that β-amyloids are neurotoxic in vitro and in vivo (Yankner, 1996), but intriguingly, cognitive impairments precede high levels of β-amyloid accumulation. Thus, the classical amyloid hypothesis (Tanzi and Bertram, 2005) cannot explain all the molecular and cellular events occurring in the different forms of AD (Drouet et al., 2000; Lee et al., 2006). Several mechanisms probably account for this multifactorial pathology. Stress for example is another well known factor able to modify neuronal plasticity and hippocampus aging from the pioneer studies of McEwen's laboratory (Sapolsky et al., 1985; Woolley et al., 1990; Watanabe et al., 1992). It was observed that chronic stress induces atrophy of apical dendrites of CA3 pyramidal neurons in the hippocampus of male rats and tree shrews (McEwen, 1999). These processes involve glucocorti-

coids along with excitatory amino acids mediation and results in cognitive impairment in the learning of spatial and shortterm memory tasks. Chronic stress and glucocorticoids are known to promote the death of neurons and impairment of cognitive functions in a variety of experimental systems (Lupien and McEwen, 1997; Porter and Landfield, 1998) sometimes even leading to neuropsychiatric disorders (Sapolsky, 2000; Landfield et al., 2007). Chronic stress has also been reported to reduce hippocampal BDNF expression (Smith et al., 1995; Ueyama et al., 1997) although a single immobilization stress challenge induces rapid induction of BDNF expression in the hippocampus (Marmigere et al., 2003). Stress can either diminish or exacerbate the brain ageing process (de Kloet et al., 1999; Pardon, 2007) according the stimulus intensity and it represents a characteristic hormetic factor in aging. Recent data showed that glucocorticoids and stress are able to activate APP degradation providing a direct link between stress and β-amyloid accumulation (Green et al., 2006). However, it seems that the deleterious effects of stress during brain aging or AD cannot merely be explained by high levels of glucocorticoids accompanying the stress stage (Landfield et al., 2007).

7. Protective effect of BDNF against β-amyloid-induced toxicity The mechanisms by which amyloid peptides are neurotoxic are not yet understood and attempts to find protective molecules are exciting and promising. Although a substantial body of evidence has shown that BDNF protects neurons against cellular damage (Knüsel et al., 1992; Lindvall et al., 1994), we recently provided direct evidence demonstrating that BDNF has neuronal protective effects against Aβ peptide neurotoxicity in vivo and in vitro in rats (Arancibia et al., 2008). The protective effect of BDNF in vitro was demonstrated against toxicity induced by Aβ peptides on neuronal survival of primary cultures of cortical neurons. Consistent with previous observations (Geci et al., 2007; Pike et al., 1995; Yao et al., 2005) we have shown a dose-dependent toxic effect of amyloid peptides (Aβ1–42 and Aβ25 –35) in cortical neurons (Arancibia et al., 2008). Interestingly, we found that BDNF had a protective dose-response action on these neuronal toxicities, but with some differences since Aβ25–35 was more toxic for cellular survival than Aβ1–42. BDNF protection was more pronounced on toxicity induced by Aβ1–42 than that induced by Aβ25–35 since it completely reversed its toxic action whereas it partially reversed the toxicity induced by Aβ25 –35. BDNFmediated protection involves TrkB receptor activation since the effect was completely inhibited by K252a, a potent tyrosine kinase inhibitor (Koizumi et al., 1988). At similar concentrations, NGF, another neurotrophin of the same family, had a very weak effect in rescuing cells from amyloid peptideinduced death, thus indicating a specific action of BDNF. The amyloid β-derived peptide Aβ25–35 contains hydrophobic transmembrane residues 25–35 (GSNKGAIIGLM) of the Aβ protein and aggregates as insoluble fibrils (Yankner et al., 1990) that retain the toxic effect of larger Aβ peptides (Pike et al., 1993). The Aβ25–35 peptide is able to self-aggregate and induce in vivo toxicity (Maurice et al., 1996; Meunier et al.,

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2006). In addition, it has been reported that soluble Dser26Aβ1–40, which is possibly produced during aging, is released from plaques and converted by proteolysis to toxic D-ser26Aβ25–35, which enhances excitotoxicity in AD (Kubo et al., 2002). We also examined the effects of Aβ25–35 in vivo administration into the 3d ventricle or the induseum griseum (IG), combined or not with previous BDNF administration (Arancibia et al., in press). The IG is a single median cortical region which surrounds some critical regions involved in AD onset, i.e. cingular cortex, corpus callosum, and hippocampus, and represents a phylogenic old olfacto-recipient outpost of the hippocampus (Adamek et al., 1984). After Aβ25–35 administration, we observed, for example no modification in BDNF release from IG measured by push-pull perfusion in vivo, which probably indicates that there are no changes in endogenous BDNF content from this area at this Aβ25–35 concentration. In contrast, previous exogenous administration of BDNF strongly increased BDNF release according to in vitro data showing that BDNF increases in vivo BDNF release (Canossa et al., 1997). The expression of trkB.FL mRNA in cingular cortex surrounding the IG region (Fryer et al., 1996; Arancibia et al., personal observations) indicates that BDNF release may have physiological significance by activating these receptors. We also investigated the effect of β-peptides, with or without previous BDNF administration, on the number of hippocampal hilar cells expressing somatostatin mRNA. These interneurons represent a valuable parameter for investigating the toxic effect of Aβ25–35 (Aguado-Llera et al., 2007) since they are very sensitive to excitotoxicity and vulnerable to a variety of insults and neurological diseases, including AD (Chan-Palay, 1987; Ylinen et al., 1991; Lowenstein et al., 1992; Ohm, 2007; Tallent, 2007). It has been hypothesized that vulnerability of hilar somatostatin interneurons, which differs from that of interneurons from the rest of the hippocampus, is due to their lack of Ca2+ binding proteins (Tallent, 2007). The striatal-enriched protein tyrosine phosphatase (STEP), a key regulator of ERK/MAPK signaling would be involved in this excitotoxic event (Choi et al., 2007). Aβ25–35 administration significantly reduced the number of somatostatin hilar cells, in keeping with recent in vitro data (Geci et al., 2007). Interestingly, the reduction in somatostatin interneurons was completely prevented by previous BDNF administration. Somatostatin has also been described as a neurotrophic factor (Schwartz et al., 1998; Blake et al., 2004) presumably involved in the AD etiology (Dournaud et al., 1994; Vecsei and Klivenyi, 1995), notably in its early onset (Ramos et al., 2006). Moreover, it has been reported that somatostatin is involved in the catabolism of β-amyloid peptides through neprilysin activation (Saito et al., 2005), a rate-limiting enzyme for Aβ degradation (Hama and Saido, 2005). BDNF-induced somatostatin increase could result in neprilysin-mediated Aβ degradation, thus contributing to the neuroprotective effect. Moreover, TrkB.FL receptors are expressed in the hilar hippocampal region, supporting the protective effect of BDNF (Merlio et al., 1992; Yan et al., 1997). Corpus callosum damage was another of the parameters examined in our in vivo experiments after Aβ25–35 administration alone or combined with BDNF administration (Aranci-

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bia et al., in press). Its atrophy or rarefaction was shown to be a reliable and sensitive in vivo marker of early cortical neuronal loss associated with cognitive impairment in AD (Teipel et al., 1998, 2003; Hampel et al., 2002) and correlated with dementia severity in these patients (Wiltshire et al., 2005; Yamauchi et al., 2000). White matter lesions are prevalent in early stages of AD (Burns et al., 2005) but these early changes may be too subtle for detection by neuropsychological assessments, including memory test (Wang et al., 2006b). Our data showed that Aβ25–35 administration causes nuclei cell pyknosis and corpus callosum disruption, indicating fragmentation of its axonal cytoarchitecture. BDNF pre-treatment notably attenuated or abolished these Aβ25–35-induced damages. The neuronal loss that we reported in vitro and in vivo after β-amyloid treatment could be due to oxidative damage of Aβ25–35 (Stepanichev et al., 2004), which is considered to be a fundamental pathogenic mechanism of AD (Perry et al., 2004). BDNF could act as an antioxidative factor since it is known that it increases the level of activity of some antioxidant enzymes (Mattson et al., 1995). Aβ/BDNF interaction could also be explained by Aβ interference with signaling pathways used by BDNF to exert its protective effects, i.e. on BDNF-induced Arc (activity-regulated cytoskeleton-associated gene) protein expression (Wang et al., 2006a; Echeverria et al., 2007), CREB phosphorylation (Tong et al., 2004) or its nuclear translocation (Arvanitis et al., 2007). Arc synthesis controls local actin synthesis, synaptic plasticity and cognitive functions (Wang et al., 2006a) and it is known that the aging process increases cytoskeletal protein breakdown in rat brain (Bernath et al., 2006). It should be kept in mind that some protective molecules in the central nervous system whose plasma or central levels are reduced in aged or AD individuals, such as neuroactive steroids (Lamberts et al., 1997; Genazzani et al., 1998; Giordano et al., 2001; Racchi et al., 2001; Weill-Engerer et al., 2002), estrogens (Lamberts et al., 1997; Sohrabji and Lewis, 2006), NPY (Won et al., 2000; Hwang et al., 2001; Cadacio et al., 2003; Hattiangady et al., 2005), somatostatin (Burgos-Ramos et al., 2008), etc., could exert their protective effects through upstream or downstream interactions with BDNF. For example, we demonstrated in vivo in adult male rats that some neuroactive steroids, i.e. dehyroepiandrosterone (DHEA), pregnenolone (PREG), and their sulfate esters DHEA-S and PREG-S, induced significant increases in BDNF content in the hippocampus and in other regions of the central nervous system (Naert et al., 2007). Similarly, a close correlation between BDNF and NPY levels has been reported in vitro (Marty and Onteniente, 1999; Barnea et al., 2004; Wirth et al., 2005) and in vivo (Reibel et al., 2000; Hattiangady et al., 2005). Somatostatin synthesis is also increased in vitro (Rage et al., 1999) and in vivo (Carnahan and Nawa, 1995; Givalois et al., 2006) by BDNF treatment. Estrogens have been found to play a role in protecting women from some neurodegenerative disorders. A putative estrogen-response element, located on the 5′-end of exon V (Timmusk nomenclature, 1993) of the BDNF gene (Fig. 1) has been identified, which includes the start codon (ATG) for exon V (Sohrabji et al., 1995). Estrogen receptors colocalize to cells that express BDNF and TrkB. In vivo, BDNF mRNA is rapidly up-regulated in the hippocampus, cerebral cortex, amygdale

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and olfactory bulb of young ovariectomized rats exposed to estrogens and also in the entorhinal cortex of aged rats (Sohrabji and Lewis, 2006).

8.

Conclusion and prospects

Altogether, the data examined here clearly show that BDNF and/ or its receptors are impaired with aging and in AD patients. They also show that β-amyloid peptides jeopardize BDNF production and its signaling in vitro and in vivo. This fact probably engenders a dysfunctional encoding state in neurons contributing and leading to neurodegeneration (Tong et al., 2004). BDNF signaling might be impaired early in the course of AD (Murer et al., 1999). On the contrary, the exogenous addition of BDNF can rescue neurons from death by preventing β-amyloid-induced neurodegeneration in vitro and in vivo. However, in humans brain neurotrophin administration induces enormous side effects as pain and weight loss (Schulte-Herbruggen et al., 2007) limiting its possible therapeutic utilization. While BDNF is considered to provide protection against some age-induced impairments; mild exercise, mild stress or a moderate dietary restriction may contribute to hormesis in aging. Reliance on this “reserve” may reflect a form of compensation which could help subjects age gracefully. Overall, the challenge for future research will be to develop innovative therapeutical strategies aimed at boosting endogenous protective molecules, for example BDNF content or/ and its receptor activity, which certainly represents a physiological reserve for successful healthy aging.

Acknowledgments The studies from our own laboratories referred in this article were supported in part by the INSERM (France), the program ECOS-CONICYT No. C04B06 (France–Chile) end from grants from FONDECYT (Chile) (Grant #1040306) and DIPUV (Valparaiso, Chile) (15/2006, CI-1-2006).

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