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 neur
Trang 1Implication 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 disdis-ease 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.
Trang 2forms 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, cathcath-epsin-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
Trang 3cultures of cerebellar granule cells that
calpain-mediated Ca2+⁄ calmodulin-dependent protein kinase
type IV (CaMKIV) proteolysis is an autoregulatory
feedback response to sustained activation of a
Ca2+⁄ 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 Ca2+-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.
Trang 4Astrocytes 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,
Leu-norleucinal (calpain inhibitor 1) and
N-acetyl-Leu-Leu-methioninal (calpain inhibitor 2), decrease Ca2+
reperfusion-induced H2O2 production and apoptotic
cell death in cultured rat astrocytes These findings
suggest that calpain is involved in Ca2+-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
Trang 5Indeed, 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 Ca2+-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
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