Báo cáo khoa học: Implication of calpain in neuronal apoptosis A possible regulation of Alzheimer’s disease doc

MINIREVIEW Implication of calpain in neuronal apoptosis A possible regulation of Alzheimer’s disease F. Raynaud and A. Marcilhac UMR5539, EPHE-CNRS-UM2, cc107, Universite ´ de Montpellier II, France Introduction In recent years, enormous efforts have been made to clarify the apoptotic pathways involved in neuronal cell death. Indeed, programmed cell death, or apopto- sis, is beneficial during embryonic development and adult life, but its dysregulation accompanies the patho- genesis of many diseases. Calpain appears to play an important role in apoptosis in many cases, as discerned by its up-regulation and the blockade of apoptosis by calpain inhibitors. In this review, we summarize the most recent work on calpain-dependent apoptotic neuronal cell death and the regulation of intracellular pathways involving calpain which may lead to neurodegenerative patholo- gies such as Alzheimer’s disease (AD). Calpain and the regulation of apoptosis Proteolytic enzymes of the caspase family play a cen- tral role in initiating and sustaining the biochemical events that result in apoptotic cell death. In some Keywords Alzheimer’s disease; apoptosis; calpain; neurodegenerative disease; neuron Correspondence A. Marcilhac, UMR5539, EPHE-CNRS-UM2, cc107, Universite ´ de Montpellier II, place E. Bataillon, 34095 Montpellier cedex 5, France Fax: +33 0467144727 Tel: +33 0467144775 E-mail: marcilhac@univ-montp2.fr (Received 23 March 2006, accepted 31 May 2006) doi:10.1111/j.1742-4658.2006.05352.x Apoptotic neuronal cell death is the cardinal feature of aging and neurode- generative diseases, but its mechanisms remain obscure. Caspases, members of the cysteine protease family, are known to be critical effectors in central nervous system cellular apoptosis. More recently, the calcium-dependent proteases, calpains, have been implicated in cellular apoptotic processes. Indeed, several members of the Bcl-2 family of cell death regulators, nuc- lear transcription factors (p53) and caspases themselves are processed by calpains. Progressive regional loss of neurons underlies the irreversible pathogenesis of various neurodegenerative diseases such as Alzheimer’s dis- ease in adult brain. Alzheimer’s disease is characterized by extracellular plaques of amyloid–b peptide aggregates and intracellular neurofibrillary tangles composed of hyperphosphorylated tau leading to apoptotic cell death. In this review, we summarize the arguments showing that calpains modulate processes that govern the function and metabolism of these two key proteins in the pathogenesis of Alzheimer’s disease. To conclude, this article reviews our understanding of calpain-dependent apoptotic neuronal cell death and the ability of these proteases to regulate intracellular signa- ling pathways leading to chronic neurodegenerative disorders such as Alz- heimer’s disease. Further research on these calpain-dependent mechanisms which promote or prevent cell apoptosis should help us to develop new approaches for preventing and treating neurodegenerative disorders. Abbreviations AD, Alzheimer’s disease; AIF, apoptosis-inducing factor; APP, amyloid precursor protein; CaMKIV, calmodulin-dependent protein kinase type IV; cdk5, cyclin-dependent kinase 5; MAP, microtubule-associated protein; NMDAR, N-methyl- D-aspartate receptor. FEBS Journal 273 (2006) 3437–3443 ª 2006 The Authors Journal compilation ª 2006 FEBS 3437 forms of apoptosis, the extrinsic apoptotic pathway is initiated by activation of caspase 8 after death receptor ligation. In other forms, activation of the intrinsic apoptotic pathway is initiated by caspase 9 and is trig- gered by cytochrome c release from mitochondria [1]. This process is critically regulated by Bcl-2 family pro- teins. These pathways converge to activation of the executioner caspases (e.g. caspase 3). Calpains and the Bcl-2 family Members of the Bcl-2 family of proteins either promote or repress programmed cell death [2]. Several members are processed by calpains [3]. Using the model of trophic factor deprivation in sympathetic neurons, it has been shown that Bax translocation from the cytosol to the mitochondria is a critical event in neuronal apoptosis [4]. In this context, calpain cleaves Bax into a pro-apoptotic 18-kDa fragment which promotes cyto- chrome c release and apoptosis [5]. Moreover, cleavage of Bid (another pro-apoptotic Bcl-2 family member) by calpain has been implicated in mitochondrial permeabilization and cell death fol- lowing ischemia ⁄ reperfusion in the heart [6]. Indeed, truncated Bid induced cytochrome c release from brain mitochondria and apoptosis-inducing factor (AIF) release only in the presence of active calpain. AIF has been shown to translocate from mitochondria to the cytosol as well as the nucleus when apoptosis is induced. In a recent study, Polster et al. [7] suggested a novel mechanism of AIF release that is mediated by direct proteolysis of the protein by calpain, removing its association with the mitochondrial inner membrane. They proposed an experimental scheme in which the calpain 1 cleaves Bid into a more active form in order to permeabilize mitochondrial outer membrane and allow calpain access to the intermembrane space. Cal- pain 1 then cleaves AIF, releasing truncated AIF, which could regulate apoptosis. So AIF is a novel cal- pain substrate that has been implicated in neuronal cell death [7] (Fig. 1). Cross-talk between calpains and caspases The striking similarity between the substrates for casp- ases and calpains raises the possibility that both prote- ase families contribute to structural dysregulation and functional loss of nerve cells under neurodegenerative conditions. Cross-talk between calpains and caspases has been reported during apoptosis of neuronal cells induced by a prion protein fragment [8]. Moreover, calpains are able to be activated via caspase-mediated cleavage of calpastatin during initiation of apoptotic execution [9], and the disturbance of intracellular cal- cium storage associated with ischemic injury may induce apoptosis through calpain-mediated caspase 12 activation and Bcl-xL inactivation [10] (Fig. 1). Although calpains may enhance caspase activity, they can also function to block the activation of caspases. For example, calpains can cleave caspase 9 rendering it incapable of activating caspase 3 and preventing the subsequent release of cytochrome c [11]. Yamashima [12] added to this dual cross-talk another effective can- didate, cathepsins, which are implicated in neuronal cell death. He suggested a possible cascade of events involving three protease systems: calpain-induced cath- epsin release, cathepsin-mediated caspase activation and caspase-mediated calpastatin degradation leading to enhancement of calpain activity. Calpains and transcription factor regulation DNA damage is an initiator of neuronal death impli- cated in neuropathological conditions such as stroke. Previous evidence has shown that apoptotic death of embryonic cortical neurons treated with the DNA- damaging agent camptothecin is dependent on the tumor suppressor p53, an upstream death mediator, and more distal death effectors such as caspases. Calpains can act as an alternative system to the pro- teasome in regulating the stability of p53 family mem- bers. Several recent reports have highlighted a possible role for calpains in the cleavage of p53. In particular, Kubbutat & Vousden [13] have shown that a pre- ferential site for calpain cleavage exists within the N-terminus of p53. Calpain inhibition leads to p53 sta- bilization and to altered cell cycle progression. Both calpain 1 and 2 can cleave p53 with a different degree of susceptibility to cleavage in various p53 mutants. The cleavage of p53 by calpains can occur under pathological conditions and contributes to the DNA damage response [14]. More recently, Munarriz et al. [15] have shown that p73, another component of the DNA damage response, which belongs to the family of transcription factors that includes p53 and p63, is also a substrate for calpains. In this case, calpain regulation can control the steady-state protein concentration of different isoforms of p73, and calpain-mediated degra- dation of p73 may have a regulatory, physiological function, in addition to a potential role in cell death. So, several nuclear transcription factors are calpain substrates leading to the suggestion that calpains can regulate transcriptional events. Moreover, translocation of calpain to the nucleus may play a role in apoptosis. For example, Tremper-Wells & Vallano [16] have demonstrated in dissociated Calpain and neuronal apoptosis F. Raynaud and A. Marcilhac 3438 FEBS Journal 273 (2006) 3437–3443 ª 2006 The Authors Journal compilation ª 2006 FEBS cultures of cerebellar granule cells that calpain- mediated Ca 2+ ⁄ calmodulin-dependent protein kinase type IV (CaMKIV) proteolysis is an autoregulatory feedback response to sustained activation of a Ca 2+ ⁄ CaMKIV signaling pathway. (CaMKIV mediates phosphorylation of different transcription factors such as CREB and regulates expression of prosurvival ⁄ antiapoptosis genes.) Calpains, glutamate receptor and NF-jB The excitatory neurotransmitter glutamate is a key player in neuronal plasticity, development and neuro- degeneration. Stimulation of glutamate receptors [N-methyl-d-aspartate receptors (NMDARs)] leads to Ca 2+ -mediated apoptosis, a response that may contribute to excitatory neuronal toxicity. Calpain activation in neurons has been predominantly linked to cell death during ischemia and stroke [17–19]. How- ever, the literature is contradictory on this subject. Indeed, recent results show that prolonged activation of NMDARs in neurons activates calpain, and activa- ted calpain in turn down-regulates the function of NMDARs, which provides a neuroprotective mechan- ism against NMDAR overstimulation accompanying ischemia and stroke [20]. Scholzke et al. [21] have shown that glutamate activates NF-jB through calpain in neurons. Moreover, after glutamate exposure, the specific calpain inhibitor, calpeptin, prevents IjBa degradation and therefore NF-jB activation. However, the role of IjBa degradation by calpain in glutamate-induced cell death is difficult to predict as both proapoptotic and antiapoptotic effects have been attributed to NF-jB [22,23]. Fig. 1. Scheme illustrating the regulation of Bcl-2 family proteins, cytochrome c release and apoptosis by calpains. (1) Cleavage of Bax by calpain, formation of truncated Bax (tBax) and stimulation of cytochrome c release; (2) cleavage of Bid by calpain and formation of truncated Bid (tBid) leading to (2a) direct release of cytochrome c and ⁄ or (2b) permeabilization of mitochondrial outer membrane, translocation of calpain in the intermembrane space and AIF cleavage (tAIF) and release; (3) calpain-mediated Bcl-xL inactivation and cytochrome c release; (4) calpain-mediated p53 activation: p53 induces Bcl-xL inactivation, Bax stimulation and cytochrome c release. F. Raynaud and A. Marcilhac Calpain and neuronal apoptosis FEBS Journal 273 (2006) 3437–3443 ª 2006 The Authors Journal compilation ª 2006 FEBS 3439 Astrocytes contribute to the neuroprotection and survival of neurons: any astrocytic dysfunction seri- ously affects neuronal viability. The study of astrocytes is particularly important, considering the coexistence of the apoptotic death of neurons and astrocytes in damaged brains suffering from ischemia and neurode- generative diseases. Calpain inhibitors, N-acetyl-Leu- Leu-norleucinal (calpain inhibitor 1) and N-acetyl-Leu- Leu-methioninal (calpain inhibitor 2), decrease Ca 2+ reperfusion-induced H 2 O 2 production and apoptotic cell death in cultured rat astrocytes. These findings suggest that calpain is involved in Ca 2+ -mediated apoptosis in astrocytes. In this model of astrocyte apoptosis, translocation of the NF-kB p65 subunit to the nucleus is observed. These findings indicate that, in this case, NF-jB acts as a death-promoting factor in apoptosis of cultured astrocytes [24]. Calpain and Alzheimer’s neuro- degenerative disease Neuronal cell death in acute and neurodegenerative disorders occurs by a variety of biochemical and mor- phological alterations [25]. AD leads to a progressive deterioration of cognitive function with loss of memory. Neuronal injury pre- sents in the region of the brain containing the hippo- campus and the cortex. AD is characterized by two pathological hallmarks consisting of extracellular plaques of amyloid–b peptide aggregates [26] and intracellular neurofibrillary tangles composed of hyperphosphorylated microtubular protein tau [27]. The b-amyloid deposition that constitutes the plaques is composed of a 39–42 amino-acid peptide (Ab), which is the proteolytic product of the amyloid precur- sor protein (APP) by b ⁄ c secretases. Calpains modu- late processes that govern the function and metabolism of key proteins in the pathogenesis of AD including tau and APP [28]. Calpains in the brains of patients with AD Calpains are known to regulate the activities of various enzymes, including several protein kinases and phos- phatases that modify the cytoskeleton in addition to direct cleavage of cytoskeletal proteins (Lebart & Benyamin, [28a]). Alterations in calcium homeostasis in AD pathogenesis [29] associated with calpain over- activation [30] have been proposed to play an import- ant role in the development of cytoskeletal pathology and neurodegeneration. Calpain activation has been found in clinical brain specimens of AD. For example, calpain 2 was demonstrated to be present in  75% of neurofibrillary tangles [31]. Moreover, calpain 1 is acti- vated, which in turn cleaves and activates calcineurin in the AD brain and this phenomenon correlates with the number of neurofibrillary tangles [32]. Calpastatin, a specific calpain inhibitor, is altered in AD. Indeed, it decreases as the number of plaques and tangles increase in AD brains [33]. Moreover, calpain inhibi- tors were able to restore normal cognition and synap- tic transmission in a transgenic model of AD [34]. Mutations in PS1 (presenilin) that cause early onset familial AD can sensitize cells to DNA-damage- induced death and increase the production of Ab.In hippocampal neurons expressing mutant PS1, the hypersensitivity to DNA damage correlates with increased intracellular calcium concentrations, up-regu- lation of calpain 1, and induction of p53, leading to neuronal apoptosis [35]. Moreover, calpains 1 and 2 have been shown to regulate PS1 activity by direct cleavage of this protein [36]. Calpains and amyloid formations in AD Different data support the hypothesis that calpains are involved in the alpha cleavage of APP in vivo and thus are able to stimulate the nonamyloidogenic pathway, leading to a decrease in Ab42 release. Indeed, APP is cleaved within its Ab region by a-secretase to release a soluble N-terminal fragment (denoted sAPP). A number of studies have shown that enhancing a-secretase activity can reduce Ab produc- tion. APP-a processing is sensitive to a variety of regulatory agents such as phorbol esters, glutamate, calcium ionophore. For example, some authors demon- strated that the stimulated sAPP release by phorbol esters involves calpain activation in the cells, suggesting that calpain, particularly calpain 1, is a potential candi- date for an a-secretase substrate in the regulated APP a-processing [37,38]. These results support the hypothe- sis of a decrease in calpain activity during aging leading to selective accumulation of its substrates (e.g. APP) and an increase in Ab42 production in cultured cells [39]. Consistent with this, it has been reported that infusion of calpain inhibitors into the rat brain results in accumulation of Ab or Ab-containing fragments [40]. This effect is not unexpected because calpain is essential for life, and severe inhibition of its activity could be harmful to cells. Although this novel model for plaque formation is in agreement with both the property of calpain that consists of specific and limited cleavage of target proteins, and data that show that other calpain susbtrates such as spectrin (fragment) are also deposited during aging [41], this model remains controversial and awaits additional experimental tests. Calpain and neuronal apoptosis F. Raynaud and A. Marcilhac 3440 FEBS Journal 273 (2006) 3437–3443 ª 2006 The Authors Journal compilation ª 2006 FEBS Indeed, although there is evidence in favor of cal- pains acting as a-secretases, such as (a) the a-secretase cleavage site is identical with a cleavage site of calpain in protein kinase C, (b) calpains are colocalized with APP in situ in different structures including neurons, astroglia, senile plaques, and synapses, (c) some rea- gents that enhance a-secretase activity are well-known calpain activators, and (d) considering its vulnerability to oxidative stress, a-secretase may belong to the fam- ily of cysteine proteases, a serious problem with this is that calpains are intracellular and may be not able to reach the cleavage site of APP, which is located out- side of the membrane. However, in support of calpains acting as secretases is the fact that these proteases are involved in cleavage of other membrane surface pro- teins, including growth factor receptors, integrin and glutamate receptors, leading to the release of their extracellular domains [42]. During the extended time course of AD in humans, the calpain system plays multiple roles. Indeed, if reduced calpain activity were to promote AD pathol- ogy by increasing Ab42 generation, this would contrast with increased calpain activity promoting pathological changes in tau. Calpains and tau regulation in AD Based on a growing literature, cyclin-dependent kinase 5 (cdk5), which promote phosphorylation of tau, has been implicated in the pathological processes that contribute to neurodegeneration in AD. p35 is a neuron-specific activator of cdk5, and conversion of p35 into p25 by calpain-dependent proteolysis causes prolonged activation and mislocalization of cdk5. Con- sequently, the p25 ⁄ cdk5 kinase hyperphosphorylates tau, disrupts the cytoskeleton, and promotes apoptosis of primary neurons. Application of the amyloid–b-pep- tide(1–42) induces the conversion of p35 into p25 in neurons, and inhibition of cdk5 or calpain activity reduces cell death in these conditions [43,44]. More- over, a recent study showed that preaggregated Ab induced the generation of a neurotoxic 17-kDa tau fragment, which is prevented by a calpain inhibitor in cultured hippocampal neurons [45]. This proteolytic cleavage may lead to neurite degeneration by reducing the pool of full-length tau available for binding to microtubules. The decrease in tau bound to microtu- bules could in turn reduce their stability and promote a more rapid depolymerization cycle and therefore the disruption of the microtubule network [45]. Veeranna et al. [46] demonstrated that, under conditions of cal- cium injury in neurons, calpains are upstream activa- tors of Erk1,2 signaling and probably mediate, in part, the hyperphosphorylation of neurofilaments and tau seen at early stages of AD. Besides the alteration of the structure and properties of tau [the most studied member of the microtubule- associated protein (MAP) family], modifications of other members of this family (such as MAP1A, MAP1B and MAP2) may contribute to the perturba- tion of the microtubule network in AD and ultimately lead to neuronal degeneration without accumulation of amyloid deposits. A recent study [47] showed that sol- uble Ab oligomers induce time-dependent degradation of MAP1A, MAP1B and MAP2. Calpain activation is sufficient on its own to proteolyse MAP2a,b,c iso- forms, whereas MAP1A and MAP1B sequential pro- teolysis results from caspase 3 and calpain activation. This work confirms the cross-talk between caspase and calpain and identifies a novel mechanism associated with the proteolysis of several MAPs and leading to neuronal apoptosis in AD. Conclusion In summary, the ubiquitous expression of calpains in distinct subcellular compartments at different matura- tional stages and the diversity of substrates indicate that they are multifunctional effectors of myriad intra- cellular processes. Moreover, progressive cell loss in specific neuronal populations is a pathological hallmark of neurodegen- erative diseases, and calpain is a Ca 2+ -activated pro- teolytic enzyme involved in neurodegeneration in a variety of injuries and diseases of the central nervous system. Thus, identification of mechanisms that involve cal- pains and either promote or prevent cell apoptosis provides new approaches for treating diverse neuro- degenerative disorders including AD. References 1 Polster BM & Fiskum G (2004) Mitochondrial mechanisms of neural cell apoptosis. J Neurochem 90, 1281–1289. 2 Shacka JJ & Roth KA (2005) Regulation of neuronal cell death and neurodegeneration by members of the Bcl-2 family: therapeutic implications. Curr Drug Targets CNS Neurol Disord 4, 25–39. 3 Gil-Parrado S, Fernandez-Montalvan A, Assfalg- Machleidt I, Popp O, Bestvater F, Holloschi A, Knoch TA, Auerswald EA, Welsh K, Reed JC, et al. (2002) Ionomycin-activated calpain triggers apoptosis. A probable role for Bcl-2 family members. J Biol Chem 277, 27217–27226. F. Raynaud and A. Marcilhac Calpain and neuronal apoptosis FEBS Journal 273 (2006) 3437–3443 ª 2006 The Authors Journal compilation ª 2006 FEBS 3441 4 Putcha GV, Deshmukh M & Johnson EM Jr (1999) BA fX translocation is a critical event in neuronal apopto- sis: regulation by neuroprotectants, BCL-2, and cas- pases. J Neurosci 19, 7476–7485. 5 Gao G & Dou QP (2000) N-terminal cleavage of bax by calpain generates a potent proapoptotic 18-kDa fragment that promotes bcl-2-independent cytochrome C release and apoptotic cell death. J Cell Biochem 80, 53–72. 6 Chen M, He H, Zhan S, Krajewski S, Reed JC & Gottlieb RA (2001) Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia ⁄ reperfusion. J Biol Chem 276, 30724–30728. 7 Polster BM, Basanez G, Etxebarria A, Hardwick JM & Nicholls DG (2005) Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mito- chondria. J Biol Chem 280, 6447–6454. 8 O’Donovan CN, Tobin D & Cotter TG (2001) Prion protein fragment PrP-(106–126) induces apoptosis via mitochondrial disruption in human neuronal SH-SY5Y cells. J Biol Chem 276, 43516–43523. 9 Porn-Ares MI, Samali A & Orrenius S (1998) Cleavage of the calpain inhibitor, calpastatin, during apoptosis. Cell Death Differ 5, 1028–1033. 10 Nakagawa T & Yuan J (2000) Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol 150, 887–894. 11 Chua BT, Guo K & Li P (2000) Direct cleavage by the calcium-activated protease calpain can lead to inactiva- tion of caspases. J Biol Chem 275, 5131–5135. 12 Yamashima T (2000) Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates. Prog Neurobiol 62 , 273–295. 13 Kubbutat MH & Vousden KH (1997) Proteolytic clea- vage of human p53 by calpain: a potential regulator of protein stability. Mol Cell Biol 17, 460–468. 14 Sedarous M, Keramaris E, O’Hare M, Melloni E, Slack RS, Elce JS, Greer PA & Park DS (2003) Calpains med- iate p53 activation and neuronal death evoked by DNA damage. J Biol Chem 278, 26031–26038. 15 Munarriz E, Bano D, Sayan AE, Rossi M, Melino G & Nicotera P (2005) Calpain cleavage regulates the protein stability of p73. Biochem Biophys Res Commun 333, 954–960. 16 Tremper-Wells B & Vallano ML (2005) Nuclear calpain regulates Ca 2+ -dependent signaling via proteolysis of nuclear Ca 2+ ⁄ calmodulin-dependent protein kinase type IV in cultured neurons. J Biol Chem 280, 2165–2175. 17 Saido TC, Sorimachi H & Suzuki K (1994) Calpain: new perspectives in molecular diversity and physiologi- cal-pathological involvement. FASEB J 8, 814–822. 18 Wang KK (2000) Calpain and caspase: can you tell the difference? Trends Neurosci 23 , 20–26. 19 Farkas B, Tantos A, Schlett K, Vilagi I & Friedrich P (2004) Ischemia-induced increase in long-term potentia- tion is warded off by specific calpain inhibitor PD150606. Brain Res 1024, 150–158. 20 Wu HY, Yuen EY, Lu YF, Matsushita M, Matsui H, Yan Z & Tomizawa K (2005) Regulation of N-methyl- D-aspartate receptors by calpain in cortical neurons. J Biol Chem 280, 21588–21593. 21 Scholzke MN, Potrovita I, Subramaniam S, Prinz S & Schwaninger M (2003) Glutamate activates NF-kappaB through calpain in neurons. Eur J Neurosci 18, 3305– 3310. 22 Mattson MP, Culmsee C, Yu Z & Camandola S (2000) Roles of nuclear factor kappaB in neuronal survival and plasticity. J Neurochem 74, 443–456. 23 de Erausquin GA, Hyrc K, Dorsey DA, Mamah D, Dokucu M, Masco DH, Walton T, Dikranian K, Soriano M, Garcia Verdugo JM et al. (2003) Nuclear translocation of nuclear transcription factor-kappa B by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropion- ic acid receptors leads to transcription of p53 and cell death in dopaminergic neurons. Mol Pharmacol 63, 784–790. 24 Takuma K, Baba A & Matsuda T (2004) Astrocyte apoptosis: implications for neuroprotection. Prog Neurobiol 72, 111–127. 25 LeBlanc AC (2005) The role of apoptotic pathways in Alzheimer’s disease neurodegeneration and cell death. Curr Alzheimer Res 2 , 389–402. 26 Morgan C, Colombres M, Nunez MT & Inestrosa NC (2004) Structure and function of amyloid in Alzheimer’s disease. Prog Neurobiol 74, 323–349. 27 Avila J (2006) Tau phosphorylation and aggregation in Alzheimer’s disease pathology. FEBS Lett. 28 Di Rosa G, Odrijin T, Nixon RA & Arancio O (2002) Calpain inhibitors: a treatment for Alzheimer’s disease. J Mol Neurosci 19, 135–141. 28a Lebart M-C & Benyamin Y (2006) Calpain involvement in the remodeling of cytoskeletal anchorage complexes. FEBS J 273, 3415–3426. 29 Mattson MP & Chan SL (2003) Neuronal and glial calcium signaling in Alzheimer’s disease. Cell Calcium 34, 385–397. 30 Nixon RA, Saito KI, Grynspan F, Griffin WR, Katayama S, Honda T, Mohan PS, Shea TB & Beermann M (1994) Calcium-activated neutral proteinase (calpain) system in aging and Alzheimer’s disease. Ann N Y Acad Sci 747, 77–91. 31 Adamec E, Mohan P, Vonsattel JP & Nixon RA (2002) Calpain activation in neurodegenerative diseases: confo- cal immunofluorescence study with antibodies specifi- cally recognizing the active form of calpain 2. Acta Neuropathol (Berl) 104, 92–104. 32 Liu F, Grundke-Iqbal I, Iqbal K, Oda Y, Tomizawa K & Gong CX (2005) Truncation and activation of calci- neurin A by calpain I in Alzheimer disease brain. J Biol Chem 280, 37755–37762. Calpain and neuronal apoptosis F. Raynaud and A. Marcilhac 3442 FEBS Journal 273 (2006) 3437–3443 ª 2006 The Authors Journal compilation ª 2006 FEBS 33 Nilsson E, Alafuzoff I, Blennow K, Blomgren K, Hall CM, Janson I, Karlsson I, Wallin A, Gottfries CG & Karlsson JO (1990) Calpain and calpastatin in normal and Alzheimer-degenerated human brain tissue. Neuro- biol Aging 11, 425–431. 34 Battaglia F, Trinchese F, Liu S, Walter S, Nixon RA & Arancio O (2003) Calpain inhibitors, a treatment for Alzheimer’s disease: position paper. J Mol Neurosci 20, 357–362. 35 Chan SL, Culmsee C, Haughey N, Klapper W & Mattson MP (2002) Presenilin-1 mutations sensitize neu- rons to DNA damage-induced death by a mechanism involving perturbed calcium homeostasis and activation of calpains and caspase-12. Neurobiol Dis 11, 2–19. 36 Maruyama K, Usami M, Kametani F, Tomita T, Iwat- subo T, Saido TC, Mori H & Ishiura S (2000) Molecular interactions between presenilin and calpain: inhibition of m-calpain protease activity by presenilin-1, 2 and cleavage of presenilin-1 by m-, mu-calpain. Int J Mol Med 5, 269–273. 37 Chen M & Fernandez HL (2004) Stimulation of beta-amyloid precursor protein alpha-processing by phorbol ester involves calcium and calpain activation. Biochem Biophys Res Commun 316, 332–340. 38 Chen M & Fernandez HL (2005) Mu-calpain is func- tionally required for alpha-processing of Alzheimer’s beta-amyloid precursor protein. Biochem Biophys Res Commun 330, 714–721. 39 Mathews PM, Jiang Y, Schmidt SD, Grbovic OM, Mercken M & Nixon RA (2002) Calpain activity regu- lates the cell surface distribution of amyloid precursor protein. Inhibition of clapains enhances endosomal gen- eration of beta-cleaved C-terminal APP fragments. J Biol Chem 277, 36415–36424. 40 Frautschy SA, Horn DL, Sigel JJ, Harris-White ME, Mendoza JJ, Yang F, Saido TC & Cole GM (1998) Protease inhibitor coinfusion with amyloid beta-protein results in enhanced deposition and toxicity in rat brain. J Neurosci 18, 8311–8321. 41 Masliah E, Iimoto DS, Saitoh T, Hansen LA & Terry RD (1990) Increased immunoreactivity of brain spectrin in Alzheimer disease: a marker for synapse loss? Brain Res 531, 36–44. 42 Croall DE & DeMartino GN (1991) Calcium-activated neutral protease (calpain) system: structure, function, and regulation. Physiol Rev 71, 813–847. 43 Lee MS, Kwon YT, Li M, Peng J, Friedlander RM & Tsai LH (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405, 360–364. 44 Town T, Zolton J, Shaffner R, Schnell B, Crescentini R, Wu Y, Zeng J, DelleDonne A, Obregon D, Tan J & Mullan M (2002) p35 ⁄ Cdk5 pathway mediates soluble amyloid-beta peptide-induced tau phosphorylation in vitro. J Neurosci Res 69, 362–372. 45 Park SY & Ferreira A (2005) The generation of a 17 kDa neurotoxic fragment: an alternative mechan- ism by which tau mediates beta-amyloid-induced neu- rodegeneration. J Neurosci 25, 5365–5375. 46 Veeranna Kaji T, Boland B, Odrljin T, Mohan P, Basavarajappa BS, Peterhoff C, Cataldo A, Rudnicki A, Amin N, Li BS, et al. (2004) Calpain mediates cal- cium-induced activation of the erk1,2 MAPK pathway and cytoskeletal phosphorylation in neurons: relevance to Alzheimer’s disease. Am J Pathol 165, 795–805. 47 Fifre A, Sponne I, Koziel V, Kriem B, Yen Potin FT, Bihain BE, Olivier JL, Oster T & Pillot T (2006) Micro- tubule-associated protein MAP1A, MAP1B, and MAP2 proteolysis during soluble amyloid beta-peptide-induced neuronal apoptosis. Synergistic involvement of calpain and caspase-3. J Biol Chem 281, 229–240. F. Raynaud and A. Marcilhac Calpain and neuronal apoptosis FEBS Journal 273 (2006) 3437–3443 ª 2006 The Authors Journal compilation ª 2006 FEBS 3443 . caspase-mediated calpastatin degradation leading to enhancement of calpain activity. Calpains and transcription factor regulation DNA damage is an initiator of neuronal. of cal- pains acting as a- secretases, such as (a) the a- secretase cleavage site is identical with a cleavage site of calpain in protein kinase C, (b) calpains