Addressing the complex etiology of Alzheimers disease: the role of

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Future Neurology

Review

Addressing the complex etiology of Alzheimer’s disease: the role of p25/Cdk5 Alison E Mungenast1 & Li-Huei Tsai†1,2,3 Picower Institute for Learning & Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA Department of Brain & Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA 3 Howard Hughes Medical Institute, 77 Massachusetts Avenue, Cambridge, MA 02139, USA † Author for correspondence: [email protected] 1 2

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by the progressive loss of forebrain neurons and the deterioration of learning and memory. Therapies for AD have primarily focused upon either the inhibition of amyloid synthesis or its deposition in the brain, but clinical testing to date has not yet found an effective amelioration of cognitive symptoms. Synaptic loss closely correlates with the degree of dementia in AD patients. However, mouse AD models that target the amyloid-b pathway generally do not exhibit a profound loss of synapses, despite extensive synaptic dysfunction. The increased generation of p25, an activator of the cyclin-dependent kinase 5 (Cdk5) has been found in both human patients and mouse models of neurodegeneration. The current work reviews our knowledge, to date, on the role of p25/Cdk5 in Alzheimer’s disease, with a focus upon the interaction of amyloid-b and p25/Cdk5 in synaptic dysfunction and neuronal loss.

An estimated 35 million people worldwide suffer from dementia, incurring an economic burden of roughly US $604 billion for 2010 alone [301] . These numbers are predicted to rise sharply in the next 20 years, increasing to an estimated 65.7 million patients worldwide by 2030, and 115.4 million by 2050 [302] . Alzheimer’s disease (AD) represents the most common neurodegenerative disorder associated with dementia [1] and while other major causes of death have declined in the past 10 years, the incidence of AD has risen an alarming 46.1% [2] . There is currently no cure or significantly effective treatment for AD [301,3–7] . A series of promising drug trials over the past several years has ended in unanimous disappointment [8] , and the development of alternative approaches to combat this devastating disorder is an absolute necessity. In the current article, we extend upon our previous discussion of the role of cyclin-dependent kinase 5 (Cdk5) in AD [9] and delineate recent and exciting findings that hold promise for the pursuit of new paradigms in Alzheimer’s research. AD is an age-related neurodegenerative disorder associated with severe memory impairments. A prominent feature of AD is the progressive loss of forebrain neurons and deterioration of learning and memory [1] . In 1906, Alois Alzheimer described a patient who suffered from severe brain atrophy and neuronal loss, as well as from the presence of dense extracellular deposits and intracellular aggregates within the 10.2217/FNL.11.22 © 2011 Future Medicine Ltd

neurons  [10,11] . These features were eventually identified as amyloid (neuritic) plaques and neurofibrillary tangles (NFTs), respectively [12–14] , and this condition became known as Alzheimer’s disease [15] . b-amyloid

Amyloid plaques are extracellular accumulations of b-amyloid (Ab) peptides that are derived from the proteolytic processing of the amyloid precursor protein (APP) [16–19] . The first clues as to the genetic underpinnings of AD came from findings of APP mutations in certain cases of familial AD (FAD) [20–22] . Other FAD patients were later demonstrated to have mutations in Ab processing enzymes such as presenilin 1 and 2 (PS1 and PS2) [23–26] . These findings strongly implicated Ab in the etiology of AD, leading to the creation of the ‘amyloid hypothesis’, which states that Ab has an early and critical role in all forms of AD pathogenesis [27] , and precipitating an enormous effort to delineate Ab genetics as well as disease mechanisms and to create targeted therapeutics. Enzymes in involved in amyloidogenesis BACE1

Increased levels and activity of the b-secretase enzyme, commonly known as BACE1, have been found in AD brain regions that are affected by amyloid deposition [28–30] . BACE1 is the only b-secretase active in the brain [31–33] and represents the primary rate-limiting step in the Future Neurol. (2011) 6(4), 481–496

Keywords b-amyloid n BACE1 n calpain cell-cycle re-entry n DNA damage n HDAC1 n neurodegeneration n neurotoxicity n tau n

n

part of

ISSN 1479-6708

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production of Ab. The knockout of BACE1 in mouse APP models of AD, such as the Tg2576  [34] , 5XFAD [35] and APPswe/PS1DE9 mouse lines [36] , is able to ameliorate memory deficits and cognitive decline. BACE1 knockout mice are viable and fertile [32,33] , but it is yet unknown whether the prolonged suppression of BACE1 activity could have detrimental effects in humans via its other, non-APP substrates [37–42] . g-secretase

The g-secretase complex, which was originally characterized as a membrane protease that cleaves the C terminus of Ab in the membrane [43] , is composed of four proteins, including the catalytic core protein PS1 [44] . PSEN1 represents the most frequently mutated gene in familial AD; to date, over 180 different mutations have been found in human FAD cases [303] and 13 FAD-related mutations in the homologous PSEN2 gene have been described. FAD mutations in PSEN1 and PSEN2 have been suggested to alter APP processing by increasing the ratio of Ab42 :Ab40 [45] . Clinical trials

Therapies for AD have primarily focused upon either the inhibition of amyloid synthesis or its deposition in the brain [46] . A number of such drugs have reached late-stage (Phase III) clinical testing but, to date, none have demonstrated effective amelioration of cognitive symptoms  [47–55,304,305] . Although clinical trials are still ongoing for many compounds, the current lack of encouraging clinical results with amyloid-targeting drugs should motivate researchers of neurodegeneration to study alternative disease mechanisms, including those that corroborate with Ab, in the etiology of AD. Mouse APP models of AD

Transgenic mice in which Ab burdens are increased via overexpression of APP or mutations in APP, PS1 and PS2, ecapitulate many, but not all, of the symptoms of AD. Neurodegeneration in human AD is characterized by both neuronal and synaptic loss [56,57] . In most mouse models of AD, such as the PDAPP [58] , Tg2576 [59] , APP23 [60] , PS1 [61] and 5XFAD [62] models, there is a noteworthy lack of significant neurodegeneration despite a heavy Ab burden and profound cognitive decline. For example, the 5XFAD mouse model of AD carries five gene mutations in the presenilin and APP genes, and rapidly develops massive burdens of amyloidogenic Ab42 in the brain, accompanied by 482

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cognitive decline [62,63] . However, unlike most AD cases in humans [64,65] , these mice do not demonstrate a profound loss of neurons in the cortex and hippocampus, having instead neuronal loss restricted to layer V of the cortex and the subiculum [63,66] . In addition, APP mouse models do not generally exhibit the extensive tau pathology characteristic of human AD, such as hyperphosphorylated tau or NFTs. Synaptic loss closely correlates with the degree of dementia in AD patients [67] . However, with some exceptions [68] , mouse AD models that target the Ab pathway do not generally exhibit a profound loss of synapses, despite extensive synaptic dysfunction [62,69–71] . Recent work has demonstrated that pathological activities of Ab at the synapse itself may involve the binding of Ab to the receptor tyrosine kinase EphB2, which regulates NMDA receptor trafficking and function, leading to reduced NMDA receptor (NMDAR) surface expression and deficits in synaptic strength [72] . Another recently described mechanism by which Ab may injure synapses is via the nonapoptotic activation of caspase-3, which activates calcineurin and triggers the removal of the AMPA receptor (AMPAR) GluR1 subunit from the synapse [73] . Thus, without the actual loss of the synapse, Ab may lead to synaptic dysfunction via various mechanisms, including the loss of glutamate receptor surface expression. A number of investigators have concluded that mouse APP models of AD may best recapitulate the earlier stages of the disease, corresponding perhaps to symptoms of mild cognitive impairment (MCI) in humans [74–76,306] . Tau

Neurofibrillary tangles, the other major characteristic lesion of AD, are comprised of intracellular accumulations of the microtubule-associated protein tau in the soma, axons and dendrites of affected neurons [77] . Tau is involved in many different biological processes, including the stabilization of microtubules in neurons [78] , which is necessary for the proper transport of organelles and intermediate filaments to the distant domains of the neuron [79] . Tau pathology, consisting of aberrantly phosphorylated and aggregated tau, is characteristic of a number of neurodegenerative disorders, including AD [80–82] . Although tau mutations have not been found in AD, hereditary mutations in the MAPT (tau) gene have been linked to cases of frontotemporal dementia [83,84] . Overexpression of the tau protein in mouse models has been demonstrated to future science group

Addressing the complex etiology of Alzheimer’s disease: the role of p25/Cdk5

disrupt intracellular trafficking [85] and to induce axonal degeneration [86] , and mice overexpressing mutant human tau have been shown to form NFTs in vivo [87] . The extent of tau pathology in human AD has been shown to correlate well to disease severity [88] , and there has recently been renewed interest in the potential of tau as a target in a second therapeutic front against the pathology of AD [89,90] . Cdk5

The proline-directed serine/threonine kinase, Cdk5, has been well characterized as a tau kinase  [91,92] that associates with NFTs in the AD brain [93,94] . In the triple-transgenic mouse model of AD (3×Tg-AD mice), the targeted knockdown of Cdk5 has been demonstrated to relieve tau pathology [95] . While implicated as a tau kinase, Cdk5 plays physiological roles in a great number of neuronal functions. These include neurogenesis [96,97] , neuronal migration and positioning [97–101] , neuronal polarity and axon development [102,103] , vesicle trafficking  [104–109] , synaptogenesis [108,110–114] , cytoskeletal regulation [115–119] , synaptic plasticity and learning and memory [108,109,120–125] . Cdk5 has multiple roles in synaptic plasticity as well as synapse formation and function [126] and has been demonstrated to be an important regulator of synaptic homeostasis [109,127,128] . Cdk5 is activated when bound to one of its two activators, p35 or p39, which have related primary sequences [99,129–134] . Cdk5 activity is limited by the amount of available p35 protein in neurons, as indicated by excess Cdk5 relative to p35 in brain tissue [135,136] . The abundance of p35 is regulated by two alternative pathways consisting of the rapid proteasomal degradation of p35, or the direct truncation of p35 to a 25kD form by a specific protease [137,138] . p35 is cleaved by calpain to generate p25

Nearly a decade ago, it was revealed that the truncated form of p35, p25, was increased in the brains of AD patients [137,139] . This finding was the subject of some controversy and different methods of sample processing, particularly the post-mortem interval involved, appear to have contributed to the discrepancies in findings between different groups [139–143] . Subsequently, the increased generation of p25 was found in mouse models of AD [62,144–148] , ischemia [138] , amyotrophic lateral sclerosis [149] , Parkinson’s disease [150] , Huntington’s disease [151] and hippocampal sclerosis [152,153] . In cultured mouse future science group

Review

neurons, the cleavage of p35 to p25 is induced upon exposure to a number of neurotoxic insults, including hydrogen peroxide (H2O2 ; oxidative stress), glutamate (excitotoxicity), ionomycin (high internal calcium) and Ab (amyloid toxicity) [138] . Interestingly, Cdk5 activity does not appear to be required for p35 cleavage [138] . Lee et al. reported that the cleavage of p35 to p25 was inhibited by the depletion of calcium, as well as by either calpain inhibitors or the specific depletion of m-calpain, demonstrating that p25 generation is mediated by calpain in a calcium-dependent manner [138] . These findings are consistent with data demonstrating increased activity of both Cdk5 and calpain in human AD brains [154,155] . Thus, neurotoxic insults that lead to increased intracellular concentrations of calcium generate p25 via the calpain cleavage of p35. The functional consequence of p25 generation is an area of intense investigation. The truncated p25 displays a longer half-life than p35 and has a distinct subcellular localization [156] . Binding of p25 results in the prolonged activation of Cdk5 and changes its substrate specificity [137,138,157] . However, the contribution of p35 versus p25 to the various functions of Cdk5 is still unclear. The p35 protein has long been known to localize to cell membranes, both at the cell periphery, including neurites and nerve terminals [158,159] , as well as intracellular compartments such as the Golgi apparatus [160] . When p35 is cleaved to produce p25, the myristoylated portion that holds p35 to the membrane is lost [137] and p25/Cdk5 becomes a soluble complex [161] that is found both in the cytoplasm [137] as well as in the nucleus [162] , where it has been found to accumulate following neurotoxic stimuli [162,163] . Nuclear Cdk5 activity is also increased following neurotoxic stimuli [164] . Outside of the CNS, p25/Cdk5 activity in adipose tissue has recently been implicated in the pathogenesis of insulin resistance and obesity [165] . Mouse models of p25 overexpression

The concept of p25 elevation being a major factor in neurodegeneration is supported by studies of transgenic mouse models of p25 overexpression  [166,167] . In 2003, a bi-transgenic mouse model was generated that expressed a p25-GFP fusion protein in an inducible, postdevelopmental, and forebrain-specific manner (CKp25 mouse) [167] . Upon the induction of p25 expression, neurodegenerative events occur in a rapid and predictable manner (Table 1; p25 mouse models). Increased BACE1 activity and Ab www.futuremedicine.com

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Table 1. Transgenic mouse models of p25 overexpression. Mouse

Phenotype

Ref. [111,167,191,222]

CK-p25 mouse; inducible human p25 expression from CaMKII promoter

After 2 weeks: increased BACE1, Ab generation, tau phosphorylation, ectopic cell-cycle protein expression, DNA damage and enhanced synaptic plasticity After 4 weeks: astrogliosis After 6 weeks: loss of synapses and neurons, cognitive impairment and intraneuronal Ab accumulation >20 weeks: severe tau pathology

NSE-p25 mouse; constitutive expression of human p25 under the NSE promoter

Increased phosphorylation of tau and neurofilament protein, increased Ab, positive silver staining and cytoskeletal disruption in neurons, increased locomotor activity, increased phospho-STAT3, increased BACE1 and reduced GSKb3 activity

p25/APP mouse; cross of NSE-p25 and Tg2576 p25/T mouse; cross of NSE-p25 and P301L mutant tau mice

Increases in levels of b -CTF relative to a-CTF, increased BACE1 and increased sAPPb Increased hyperphosphorylated tau, increased tau aggregation and the presence of NFTs

[189]

PDGF-p25 mouse; constitutive p25 expression under the PDGF B chain promoter

Profound dyskinesia, central axonopathy and phosphorylated tau

[171]

p25.T mouse; inducible human p25 expression from the CaMKII promoter p25 mouse; constitutive expression from the CaMKII promoter

Progressive loss of hippocampal and cortical neurons beginning at 2 weeks of p25 expression, excitotoxicity markers and gliosis Lower p25 levels than other models, increased phosphorylation of neurofilament M, increased tau protein, improved performance on Morris water maze and improved performance fear conditioning test

[152] [177]

pCMV-p25 mouse; constitutive expression of bovine p25 from the CMV promoter

Pituitary gland hyperplasia, early mortality and ataxia

[176]

[166,172,189]

[173]

APP: Amyloid precursor protein; CMV: Cytomegalovirus; NFT: Neurofibrillary tangle; NSE: Neuron-specific enolase; sAPPb: C-terminally truncated soluble APP.

generation are evident by 2 weeks of induction, astrogliosis is observed after 4 weeks of induction, neuronal loss and cognitive impairment are appreciable after 6 weeks of p25 induction, and severe tau pathology is evident after prolonged (>20 weeks) p25 expression [111,167] . Although these mice accumulate intraneuronal Ab and extracellular Ab filaments, Ab plaques do not develop. In addition, following p25 induction, neurons aberrantly express cell cycle proteins and form dsDNA breaks at an early stage prior to their death. The onset of p25 overexpression is followed by the eventual death of nearly 40% of hippocampal and cortical neurons in this mouse model. Unlike most APP mouse models, the CK-p25 mice demonstrate significant tau pathology, including tau hyperphosphorylation and impaired microtubule polymerization [167] . Other Cdk5 target proteins implicated in neuro­degenerative disease, such as neurofilament H (NFH) [168] and APP [169,170] , are also differentially phosphorylated in the CK-p25 brain compared with controls. Two independent mouse models of p25 overexpression, the neuron-­specific enolase (NSE)-p25 and PDGF-p25 mouse lines, further support the role of p25 in neurodegeneration, 484

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with similar findings of hyperphosphorylated tau and neurofilament in the brain, although NFTs are absent in these models [166,171] . In addition, in the NSE-p25 mouse model, differences in tau phosphorylation between transgenic and wildtype mice disappear by 12 months of age [172,173] . The overexpression of p35/Cdk5 with human tau in 3×Tg mice does not lead to tau pathology and neurodegeneration [174] , indicating that p35/Cdk5 is not a major tau kinase. These findings are supported by biochemical work in which it was demonstrated that the p25/Cdk5 complex has much greater activity as a tau kinase than does p35/Cdk5 [173–175] . By contrast, another inducible mouse model of p25 overexpression, which displays severe neurodegeneration characterized by profound neuronal loss and the near-elimination of the hippocampus, did not demonstrate elevations of Ab or tau phosphorylation [152] . In addition, a mouse model in which bovine p25 was expressed using a cytomegalovirus promoter displayed severe ataxia and early mortality without neurodegeneration [176] . Although prolonged expression of high levels of p25 lead to cognitive decline in mouse models, short-term or low levels of p25 expression in transgenic mice may have a beneficial future science group

Addressing the complex etiology of Alzheimer’s disease: the role of p25/Cdk5

effect on cognition [111,177] . Interestingly, the disparate findings from different p25 transgenic mice appear to indicate a milder phenotype for models with constitutive  [166,171] versus induced  [152,167] p25 over­expression, indicating the potential for developmental compensation by unknown mechanisms. The relationship between p25/Cdk5 & Ab p25 production is induced by Ab

The role of p25/Cdk5 as a key player in neurodegeneration has supported a dynamic and promising area of AD research in recent years, owing to its potential implications in both Ab and tau pathologies. Exposure to Ab reliably raises p25 levels in cultured neurons as a direct result of increased calpain activity [138,178] . The mechanism by which Ab causes dysregulation of calcium homeostasis in neurons has been under investigation for more than two decades [179] , and may involve numerous calcium sources, such as both NMDARs and AMPARs [180] , Group I metabotropic glutamate receptors (mGluRs) [181] , cation channels such as the pentameric a7 nicotinic acetylcholine receptor (a7nAChR) [182,183] , the increase of extracellular glutamate via the oxidative disruption of astrocytic glutamate transporters [184–186] and even direct membrane disruption [187] . The accumulation of p25 induced by elevated Ab is also abundantly reported in mouse models of AD, including the 5XFAD, Tg2576, 3xTg‑AD and PS cDKO lines [62,145,146,188] . Together, these observations provide strong evidence that Ab generation leads to calpain activation and p25 accumulation, events that are likely to play a role in the pathogenesis of AD. Ab generation is upregulated by p25/Cdk5

Numerous reports have demonstrated that p25/ Cdk5 increases Ab production both in vitro and in vivo [189–191] . Mouse models of p25 overexpression, such as the CK-p25 and the NSE-p25 mice, express increased levels of Ab [166] . The inhibition of Cdk5 activity in transgenic p25 mice reduces Ab1–42 production [172] , suggesting that Ab1–42 processing is influenced by the p25/Cdk5 complex. Two plausible mechanisms may account for the upregulation of Ab production by p25/Cdk5. The differential phosphorylation of APP plays a role in its internalization as well as in the generation of secreted APP and Ab [192–195] . The threonine 668 (Thr668) residue of APP is phosphorylated in vivo by a number of protein kinases, including Cdk5 [196] . The overexpression of p25 in neurons increases phosphorylation of APP on Thr668 and future science group

Review

enhances the secretion of Ab [190] . In addition, the pharmacological inhibition of Cdk activity, or the expression of an alanine mutant of APP Thr668 in cortical neurons, reduces Ab generation in cultured neurons [195] . Consistent with the possibility that APP phosphorylation mediates Ab accumulation, the phosphorylation of APP at Thr668 is significantly increased in the hip���� pocampus of patients with AD [195] . Alterations in Cdk5 activity, resulting from p25 generation, may therefore induce pathological Ab generation via phosphorylation of APP. Another mechanism by which p25/Cdk5 activity may affect Ab levels is via the regulation of BACE1. The levels and activity of BACE1 protein are increased in AD patient brains [28,197] , particularly around amyloid plaques [198] . In the NSE-p25 Tg mice, it was reported that levels of Bace1 mRNA and protein are increased via the hyperphosphorylation of Stat3 by Cdk5 [189] . Thus, in addition to the direct phosphorylation of APP by Cdk5, Cdk5 activity may increase Ab by increasing the expression of BACE1. The interplay between Ab & p25 in the pathogenesis of AD

Mouse CNS phenotypes that result from the manipulation of APP predominantly consist of Ab pathology, synaptic dysfunction and cognitive decline. By contrast, several p25 transgenic mouse models demonstrate an extensive loss of synapses, profound neuronal loss and tau pathology, in addition to Ab generation [111,167] . Thus, the induction of Ab pathology appears to recapitulate symptoms of MCI, whereas the overexpression of p25 induces both the phenotype of Ab pathology (synaptic dysfunction and cognitive impairment) as well as leading to severe neurodegeneration. The findings that increasing p25 leads to Ab generation, and vice versa, indicates that these two molecules are inexorably linked in a vicious feedback cycle, each increasing the other to accelerate AD-like pathology. Therefore, in terms of therapeutic targets, the prevention of Ab accumulation and synaptic dysfunction, as well as the prevention of synaptic and neuronal loss, may all be achieved via the reduction of neuronal p25 generation. The role of p25/Cdk5 in DNA damage & cell-cycle re-entry in neurons during neurodegeneration Ectopic cell cycle re-entry in AD

A role for aberrant cell-cycle re-entry in AD was proposed following the first observations of hyperphosphorylated tau, a form of tau www.futuremedicine.com

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protein normally found only in dividing cells, in the brains of AD patients [199,200] . It has since become clear that, in neuropathologies involving neuronal loss, such as ischemic stroke [201–203] , Parkinson’s disease [204,205] , Huntington’s disease [206] , amyotrophic lateral sclerosis [207,208] and AD [209–213] , neurons engage in aberrant cell cycle activities, expressing cell cycle markers such as Ki-67 [210,214] and proliferating cell nuclear antigen [210,211] , and synthesizing DNA [215–218] . The overexpression of oncogenes and cell cycle genes in neurons leads to neuronal death both in vitro and in vivo [211] . AD brains appear to have an increased incidence of aneuploid neurons that also express cyclin B1, indicating cell cycle activation and DNA replication without cell division [213,219] . Previous studies have suggested that, although neurons exhibiting cell cycle reactivation markers may be selected to die in AD, the process of neuronal death may be years, or even decades, in duration [213,219,220] . Therefore, aberrant neuronal cell-cycle activation is an attractive mechanism with which to explain neuronal loss in age-related neurodegenerative disorders such as AD. The activities of p35/Cdk5 play a significant role in keeping the cell cycle in check in the mature neuron [221] . However, in the presence of p25, this regulation appears to be dysfunctional. In CK-p25 transgenic mice, high levels of p25 lead to ectopic cell-cycle protein expression that precedes neuronal death by several weeks  [222] , indicating that cell cycle re-entry is an early, rather than a terminal, event in neurodegeneration. In addition, p25/Cdk5 is a positive regulator of Ab-induced cell-cycle reactivation in neurons, a process which can be blocked using inhibitors of calpain or Cdk5 [223] . APP transgenic mouse models express ectopic cell cycle proteins [224,225] , and mutations in the presenilin genes lead to chromosome instability [226–228] . It is interesting that, although some APP mouse models have neuronal cell-cycle reactivation, there is little neuronal loss, and the incidence of DNA damage in APP mouse models has not been well characterized. Loss of genome integrity in neurodegeneration

DNA can be altered by cell processes such as oxidation. Oxidative damage can lead to singlestrand DNA breaks (SSBs), which can progress to double-strand breaks (DSBs)[229,230] . A number of genetic neurological disorders that manifest with progressive neurodegeneration result from specific defects in DNA repair [231] . These include spinocerebellar ataxia (SCAN1) [232] and ataxia 486

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oculomotor apraxia [233] , in which SSB repair is defective, as well as disorders in which DSB repair is specifically impaired, such as ataxia telangiectasia and ataxia telangiectasia-like disorder [234,235] . In addition, in the aged human brain, there is an increased accumulation of oxidative DNA damage in the regulatory regions of genes involved in learning and memory processes, compared with younger brains, which probably impairs synaptic function [236] . A variety of accelerated aging syndromes that are associated with neurodegeneration, such as Werner syndrome, are caused by mutations in DNA repair genes [237–239] . Therefore, normal aging and neurodegeneration appear to share the common characteristic of impaired DNA damage repair. Cells vary widely in their responses to DNA lesions and the death of the cell is not an inevitable consequence of damage [240] . DNA damage has been demonstrated to activate cell ������������������� death��������� in postmitotic neurons [241] , but the incidence of DNA damage does not necessary lead to the death of the cell and it is still an open question as to how much, and what kind of, DNA damage neurons can sustain before dying. It is likely, though, that an increase in unrepaired DSBs can spell death for the neuron, as this type of damage is not tolerated by any cell type [242,243] . In addition, DNA damage that is followed by the ectopic expression of cell-cycle proteins appears likely to result in the eventual death of the neuron [244] . Neurons are particularly vulnerable to DNA damage in those regions of the brain that are most affected in AD, such as the hippocampus [245–247] , and an increased accumulation of DNA damage may be an early event in the pathology of AD [248] . p25/Cdk5 induces neuronal DNA damage via the inhibition of HDAC1

In the CK-p25 mouse model of AD, the overexpression of p25 in excitatory neurons leads to ectopic cell-cycle protein expression as well as the formation of DNA DSBs prior to neuronal death  [222] . At an early (2-week induction) time point of the CK-p25 model, robust immunoreactivity for the DSB marker phospho-serine 129 histone H2AX (gH2AX) was detected. The activation of the DNA damage response was confirmed by the increase in a number of damage response proteins, including Rad51 and DNA Pol e [222] . Interestingly, the DNA damage and cellcycle reactivation observed in CK-p25 neurons was reversible upon the cessation of p25 induction, indicating the presence of a therapeutic window between the onset of genome instability and neuronal death. future science group

Addressing the complex etiology of Alzheimer’s disease: the role of p25/Cdk5

In examining the mechanism underlying p25induced DNA damage in the CK-p25 mouse, it was demonstrated that histone deacetylase 1 (HDAC1), a nuclear protein [249] , can be directly inhibited by an interaction with p25 at its catalytic domain. HDAC1 has been demonstrated to be important in the transcriptional repression of cell cycle-related genes such as p21/WAF, cyclins A, D and E, and cdc25A [250–252] . It was demonstrated that the inactivation of HDAC1 via short-hairpin RNA (shRNA) knockdown or pharmacological inhibition resulted in DSBs, aberrant cell cycle protein expression and neuronal death [222] . Importantly, restoring HDAC1 activity by overexpressing wild type HDAC1 rescued neurons from DSBs and cell death in 6-week-induced CK-p25 mice. The striking actions of p25 at the level of chromatin remodeling provide a molecular mechanism for the neurodegeneration phenotype that is observed in CK-p25 animals and AD patient brains.

Ca2+ Calpain

p35

Cdk5 p25

Altered localization Prolonged Cdk5 activity

Increased Aβ Phosphorylated tau Synaptic dysfunction Cognitive decline

p25/Cdk5 impairs DNA base-excision repair

The activation of Cdk5 by p25 may also lead to impaired DNA repair in neurons via the disruption of Cdk5 activity in the base-excision repair pathway, an important mechanism for the repair of oxidative damage to neuronal DNA. The base-excision repair pathway protein, Ape1, is crucial for the repair of DNA damaged by oxidative stress and its phosphorylation by Cdk5 results in accumulation of DNA damage, leading to neuronal death [253] . In addition, phosphorylated Ape1, but not total Ape1, was significantly elevated in the nuclei of pyramidal neurons in the hippocampus of AD patients [253] . It remains to be determined whether Ape1 is a nuclear Cdk5 target specific to p25/Cdk5. p25/Cdk5 links DNA damage to ectopic cell-cycle protein expression & neuronal death via ataxia: telangiectasia mutated

In 2009, Tian et al. demonstrated that, following DNA damage, Cdk5 directly phosphorylates the phosphatidylinositol-3-kinase-like kinase, ataxia telangiectasia mutated (ATM) in postmitotic neurons [254] . Following the induction of DSBs, the ATM protein is activated and phosphorylates a number of proteins that control cell cycle checkpoints, DNA repair and induce cell death following DNA damage [255,256] . The inhibition of ATM in cultured neurons prevents cell-cycle re-entry and death following DNA damage [244] . Interestingly, the inhibition of Cdk5-mediated ATM phosphorylation in neurons is protective future science group

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HDAC1 loss of function Impaired DNA repair Cell cycle re-entry Neuronal death Phosphorylated tau

Figure 1. Model for the actions of p25/Cdk5 in the pathogenesis of Alzheimer’s disease. The Cdk5 kinase, upon activation by p25, contributes to neurodegeneration via two parallel processes. (A) p25/Cdk5 increases Ab production, which contributes to synaptic impairment and memory loss. Increased Ab, in turn, feeds back to increase p25 generation. (B) p25/Cdk5 in the nucleus inhibits HDAC1 activity, which leads to increased DNA damage and the ectopic expression of cell cycle genes, eventually leading to neuronal death. Cdk5: Cyclin-dependent kinase 5; HDAC1: Histone deacetylase 1.

against cell-cycle re-entry and p53-mediated cell death [254] . While nuclear p25/Cdk5 may phosphorylate both HDAC1 and ATM, HDAC1 has also been demonstrated to interact directly with the N terminus of ATM [257] . These interactions at the chromatin between p25/Cdk5, HDAC1 and repair enzymes such as ATM merit further examination. Box 1. Characteristics of p25. p25 is generated by the cleavage of p35 by the calcium-activated protease calpain [137,138,161] n p25 accumulates in the nucleus following toxicity [163,262] n p25 is increased in human Alzheimer’s disease (AD) brains [137,139,142] n p25 is increased in mouse AD models [62,145,146,148,188] n p25 is increased in cultured neurons by Ab administration [138,178] n p25 overexpression in transgenic mice leads to neuropathology [152,166,167,171,222] n p25 activation of cyclin-dependent kinase 5 is associated with cell-cycle reactivation in neurons [222] n p25 increases amyloid precursor protein phosphorylation and Ab secretion [190] n p25 induces increases in BACE1 expression [189] n p25 induces ectopic neuronal expression of cell cycle proteins [176,222,223] n p25 overexpression leads to increased DNA damage in neurons [222] n

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Conclusion & future perspective

To date, studies have suggested that p25 may be an upstream regulator of two distinct pathways underlying the symptoms of AD: an Ab-mediated pathway leading to synaptic dysfunction and cognitive decline, and a second pathway leading to neuron death via HDAC1 inhibition and a dysregulated DNA damage response (Figure 1) . The accumulation of Ab, stimulated by increasing p25 levels, appears

to lead to synaptic dysfunction and symptoms in mice that closely model human MCI. The nuclear activities of p25/Cdk5 appear to interfere with DNA repair pathways, leading to the aberrant reactivation of cell-cycle proteins that may be a harbinger of neuronal death. Future work should be directed towards testing this two-pathway hypothesis of p25/Cdk5 in AD. For example, it is unknown exactly how the inactivation of HDAC1 leads to DSB formation

Executive summary Alzheimer’s disease Alzheimer’s disease (AD) represents the most common neurodegenerative disorder associated with dementia, with an estimated 46.1% rise in incidence. There is currently no cure or significantly effective treatment for AD. n In the current article, we extend upon our previous discussion of the role of cyclin-dependent kinase 5 (Cdk5) in AD and delineate recent and exciting research that holds promise for the pursuit of new paradigms in Alzheimer’s research. n

Ab, BACE1, g-secretase, clinical trials, mouse amyloid precursor protein models of Alzheimer’s disease & tau Although clinical trials are still ongoing for many compounds targeting b-amyloid (Ab), no drug has yet shown an effective amelioration of cognitive symptoms. n Mouse AD models that target the Ab pathway generally do not exhibit a profound loss of synapses, despite extensive synaptic dysfunction. n

Cdk5 & the generation of p25 during neurotoxicity: transgenic p25 mice Cdk5 plays physiological roles in a great number of neuronal functions including synaptic plasticity, learning and memory and cell cycle control. n Cdk5 is activated when bound to one of its two activators, p35 or p39. n The truncated form of p35, p25, is increased in the brains of AD patients and mouse AD models. n In neurotoxic conditions, p25 generation is mediated by calpain in a calcium-dependent manner. n The truncated p25 is more stable and accumulates in the nucleus following neurotoxic stimuli. n Mouse models of p25 overexpression display cognitive decline and varying degrees of Ab and tau pathology. Transgenic CK-p25 mice exhibit severe neurodegeneration. n

The relationship between p25/Cdk5 & Ab p25 production is induced by Ab. Ab generation is upregulated by p25/Cdk5 via mechanisms including amyloid precursor protein (APP) phosphorylation and the increased expression of BACE1.

n

n

The role of p25/Cdk5 in aberrant cell cycle re-entry & DNA damage Ectopic cell cycle re-entry occurs in AD. AD is accompanied by the loss of genome integrity. n DNA damage plays a role in neurodegeneration. n DNA damage and cell cycle re-entry is mediated via the inhibition of histone deacetylase 1 by p25. n The activity of p25/Cdk5 in the nucleus can also interfere with base-excision repair. n p25/Cdk5 may dysregulate ATM to lead to the accumulation of DNA damage. n

n

Future directions for the study of p25/Cdk5 in Alzheimer’s disease p25/Cdk5 may be a promising target for the therapy of AD. There are as yet no effective Cdk5-specific inhibitors and it is also necessary to target p25/Cdk5, while leaving p35/Cdk5 function intact. n Promising future therapies may include allosteric inhibitors of Cdk5 that interfere with the p25/Cdk5 interaction. n n

Conclusion There is currently no effective treatment for AD. Clinical trials that have focused on the amelioration of Ab pathology have, to date, been disappointing. n Mouse models that manipulate APP processing cannot fully represent a complete model of AD as they lack neurodegeneration. n The Cdk5 activator p25 is produced under neurotoxic conditions and is elevated in AD patient brains and mouse AD models. n The overexpression of p25 in mice recapitulates neuronal and synaptic loss, as well as Ab and tau pathology. n The actions of p25/Cdk5 may represent the starting point for two parallel pathways in the etiology of AD. One pathway leads to Ab-mediated synaptic dysfunction, the other to DNA damage and neuronal death. n n

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in neurons, and it is not yet clear whether the DNA damage observed in the CK-p25 model of neurodegeneration is due to delayed DNA repair or the increased susceptibility of the DNA to damage. The relationship between DNA damage and neuronal death also remains to be elucidated. The activity of p25/Cdk5 may lead to neuronal loss not so much as a result of alterations in DNA damage, but from the dysfunction of the DNA damage response, which may lead to cell-cycle reactivation. In addition, although a number of reports have demonstrated a reciprocal relationship between Ab and p25 production, further mechanistic studies are necessary to determine the sequalae of interactions between these molecules early in AD-like neuropathology.

The research summarized in this article leads to the conclusion that p25/Cdk5 may be a promising target for the therapy of AD (Box 1) . Although pharmacological inhibition of overall Cdk5 activity has proven protective in mouse models, there are as yet no effective Cdk5-specific inhibitors [258,259] , and the use of more general Cdk inhibitors, such as roscovitine, would have unacceptable effects on synaptic physiology and neuronal function. Zheng et al. found that a 125-residue peptide fragment of p35, termed Cdk5 inhibitory Papers of special note have been highlighted as: n of interest

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Acknowledgement

Financial & competing interests disclosure

Support comes from NIH RO1NS051874 and NIH PO1AG27916 to L-H Tsai. L-H Tsai is an investigator of the Howard Hughes Medical Institute. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. donepezil, rivastigmine and galantamine. Int. Psychogeriatr. 21(5), 813–824 (2009).

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peptide (CIP), was a highly effective inhibitor of Cdk5 activity in cultured neurons, but its in vivo effectiveness was not demonstrated [260] . Recent work found that a much smaller p35 fragment, p5, could also inhibit Cdk5 activity in cultured neurons [261] . This small peptide may be a potential candidate for Cdk5 inhibition in vivo. A difficulty arises when one considers the necessity of targeting the activities of Cdk5 that result from its interaction with p25, while leaving p35/Cdk5 function intact. Additional promising therapies may include allosteric inhibitors of Cdk5 that interfere with the p25/Cdk5 interaction, and this is currently an active area of research interest.

We would like to thank R Madabhushi, K Ota and S Su for their insightful comments on this manuscript.

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n

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