Inhibition of tau phosphorylating protein kinase cdk5 prevents β‐amyloid‐induced neuronal death

Álvarez, Alejandra; Toro, Rodrigo; Cáceres, Alfredo; Maccioni, Ricardo B.

doi:10.1016/s0014-5793(99)01279-x

Cited by 218 publications

(168 citation statements)

References 42 publications

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“…A␤ neurotoxicity has been reported to result in tau hyperphosphorylation (11)(12)(13)(14)(15)(16)(17)(18). In agreement with these findings, we have previously shown that the addition of fibrillar A␤ to mature hippocampal neurons kept in culture for more than 28 days resulted in the sustained activation of MAPK (14,18).…”

Section: Fibrillar A␤ Activated Mapk In Hippocampal Neurons Obtained supporting

confidence: 79%

“…In addition, several groups have reported that kinases known to phosphorylate tau in vitro were activated in response to fibrillar A␤ deposition. When young neurons were incubated in the presence of fibrillar A␤, both GSK3␤ and CDK5 were activated (11,17). In mature hippocampal neurons, on the other hand, fibrillar A␤-induced neurotoxicity was accompanied by the sustained activation of mitogen-activated protein kinase (MAPK) (14)(15)(16)18).…”

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confidence: 99%

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Tau is essential to β-amyloid-induced neurotoxicity

Rapoport

Dawson

Binder

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

739

527

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Senile plaques and neurofibrillary tangles, the two hallmark lesions of Alzheimer's disease, are the results of the pathological deposition of proteins normally present throughout the brain. Senile plaques are extracellular deposits of fibrillar ␤-amyloid peptide (A␤); neurofibrillary tangles represent intracellular bundles of self-assembled hyperphosphorylated tau proteins. Although these two lesions are often present in the same brain areas, a mechanistic link between them has yet to be established. In the present study, we analyzed whether tau plays a key role in fibrillar A␤-induced neurite degeneration in central neurons. Cultured hippocampal neurons obtained from wild-type, tau knockout, and human tau transgenic mice were treated with fibrillar A␤. Morphological analysis indicated that neurons expressing either mouse or human tau proteins degenerated in the presence of A␤. On the other hand, tau-depleted neurons showed no signs of degeneration in the presence of A␤. These results provide direct evidence supporting a key role for tau in the mechanisms leading to A␤-induced neurodegeneration in the central nervous system. In addition, the analysis of the composition of the cytoskeleton of tau-depleted neurons suggested that the formation of more dynamic microtubules might confer resistance to A␤-mediated neurodegeneration.R ecent research on the field of Alzheimer's disease (AD) has been focused on the mechanisms leading to the formation of senile plaques and neurofibrillary tangles, the two hallmark lesions of this neurodegenerative disease. Both lesions are the result of the pathological deposition of proteins normally distributed throughout the brain. Senile plaques are extracellular deposits of fibrillar ␤-amyloid peptide (A␤), a cleavage product of the amyloid precursor protein (see refs. 1-5 and refs. therein). Neurofibrillary tangles, on the other hand, are intracellular bundles of self-assembled hyperphosphorylated tau proteins (6-10). Although these two lesions are often present in the same brain areas, a mechanistic link between them has yet to be established. Indirect evidence from several studies using cultured neurons suggests a role for tau in the generation of dystrophic neurites in the presence of fibrillar A␤. The common picture emerging from these studies indicates that deposition of fibrillar A␤ induces phosphorylation of tau followed by progressive degeneration of neuronal processes (11-16). In addition, several groups have reported that kinases known to phosphorylate tau in vitro were activated in response to fibrillar A␤ deposition. When young neurons were incubated in the presence of fibrillar A␤, both GSK3␤ and CDK5 were activated (11, 17). In mature hippocampal neurons, on the other hand, fibrillar A␤-induced neurotoxicity was accompanied by the sustained activation of mitogen-activated protein kinase (MAPK) (14)(15)(16)18). Taken collectively, these results suggest a key role for tau in the generation of dystrophic neurites in response to fibrillar A␤ treatments. To obtain direct ev...

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Section: Fibrillar A␤ Activated Mapk In Hippocampal Neurons Obtained supporting

confidence: 79%

mentioning

confidence: 99%

Tau is essential to β-amyloid-induced neurotoxicity

Rapoport

Dawson

Binder

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

739

527

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“…Nevertheless, overexpression of p25 in cultured neurons leads to cytoskeletal disruption, hyperphosphorylated Tau, and apoptotic cell death (16). Cdk5 activity is deregulated in hippocampal neurons by A␤ fibrils, resulting in the activation of Cdk5 and hyperphosphorylation of Tau (68,69). Probably because of its multifunctional role in the nervous system, aberrant Cdk5-p25 activity looms as a major factor in neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 99%

A 24-Residue Peptide (p5), Derived from p35, the Cdk5 Neuronal Activator, Specifically Inhibits Cdk5-p25 Hyperactivity and Tau Hyperphosphorylation

Zheng

Amin

et al. 2010

Journal of Biological Chemistry

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The activity of Cdk5-p35 is tightly regulated in the developing and mature nervous system. Stress-induced cleavage of the activator p35 to p25 and a p10 N-terminal domain induces deregulated Cdk5 hyperactivity and perikaryal aggregations of hyperphosphorylated Tau and neurofilaments, pathogenic hallmarks in neurodegenerative diseases, such as Alzheimer disease and amyotrophic lateral sclerosis, respectively. Previously, we identified a 125-residue truncated fragment of p35 called CIP that effectively and specifically inhibited Cdk5-p25 activity and Tau hyperphosphorylation induced by A␤ peptides in vitro, in HEK293 cells, and in neuronal cells. Although these results offer a possible therapeutic approach to those neurodegenerative diseases assumed to derive from Cdk5-p25 hyperactivity and/or A␤ induced pathology, CIP is too large for successful therapeutic regimens. To identify a smaller, more effective peptide, in this study we prepared a 24-residue peptide, p5, spanning CIP residues Lys 245 -Ala 277 . p5 more effectively inhibited Cdk5-p25 activity than did CIP in vitro. In neuron cells, p5 inhibited deregulated Cdk5-p25 activity but had no effect on the activity of endogenous Cdk5-p35 or on any related endogenous cyclin-dependent kinases in HEK293 cells. Specificity of p5 inhibition in cortical neurons may depend on the p10 domain in p35, which is absent in p25. Furthermore, we have demonstrated that p5 reduced A␤(1-42)-induced Tau hyperphosphorylation and apoptosis in cortical neurons. These results suggest that p5 peptide may be a unique and useful candidate for therapeutic studies of certain neurodegenerative diseases.The activity of Cdk5, a multifunctional serine/threonine kinase, is critical for neuronal development and synaptic activity; it sustains neurite outgrowth, neuronal migration, cortical lamination, and survival (1-9). Its activity depends on the binding of its neuron-specific, cyclin-related activators, p35 and p39 (10, 11). Cdk5 has also been implicated as a key player in learning and memory (12-15).Normally, Cdk5 activity is tightly regulated, but under conditions of neuronal stress, it is deregulated, leading to hyperactivity, neuronal pathology, and cell death. Accordingly, Cdk5 has been implicated in certain neurodegenerative disorders, such as AD.2 A model of the role of Cdk5 in neurodegeneration suggests that a stress-induced influx of calcium ions into neurons activates calpain, a Ca 2ϩ -activated protease, which cleaves p35 into p25 and a p10 fragment. p25, in turn, forms a more stable Cdk5-p25 hyperactive complex, which hyperphosphorylates Tau and induces cell death (16 -21). Indeed, increased levels of p25 and Cdk5 activity have been reported in AD brains. The finding that p25 may be toxic comes from studies of cortical neurons treated with ␤-amyloid (A␤), a key marker of AD pathology, where p35 is converted to p25 accompanied by activated Cdk5, Tau hyperphosphorylation, and apoptosis (22,23).Expression of the Cdk5-p25 complex seems to be primarily responsible for the Tau pathology ...

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“…In contrast, 32 Many of the pathologic epitopes on hyperphosphorylated tau in the brains of Alzheimer's disease patients were thought to be generated by sequential phosphorylation by different tau kinases. For example, phosphorylation of a specific amino acid residue by CDK5 is a prerequisite for the subsequent kinase action of glycogen synthase kinase-3␤ (22,23 The association of CDK5 with a particular activator unit, p35 or p25, provides a novel mechanism of controlling kinase characteristics.…”

Section: Discussionmentioning

confidence: 99%

Truncation of CDK5 Activator p35 Induces Intensive Phosphorylation of Ser202/Thr205 of Human Tau

Hashiguchi

Saito

Hisanaga

et al. 2002

Journal of Biological Chemistry

133

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Hyperphosphorylated tau is a major component of neurofibrillary tangles, one of the hallmarks of Alzheimer's disease. CDK5 is a kinase that phosphorylates the tau protein, and its endogenous activator, p35, regulates its activity. Recently, calpain was found to digest p35 to its truncated product, p25. Several lines of evidence suggest that p25-CDK5 has much more powerful kinase activity and that it may cause abnormal hyperphosphorylation of tau. In this study, we have examined the kinetic characteristics of in vitro phosphorylation of the longest isoform of human tau by CDK5 and its activators using recombinant proteins. Although the kinase activity of CDK5 in phosphorylating tau was significantly higher in the presence of p25, the affinity of CDK5 for tau was not different. Aberrant phosphorylation of the tau protein is considered to play a decisive role in the pathogenesis of neurodegenerative disorders collectively called tauopathies (1). Tau is a neuronspecific, microtubule-associated protein that plays major roles in the assembly and stabilization of microtubules. In the brains of patients with Alzheimer's disease, abnormally phosphorylated tau protein, paired helical filament (PHF) 1 tau, becomes dissociated from neuronal microtubules and accumulates in PHFs, the filamentous network generated by self-aggregation of hyperphosphorylated forms of tau. All six adult isoforms of tau are known to be hyperphosphorylated in PHFs (2).Several lines of evidence suggest that proline-directed serine/threonine kinases, together with protein phosphatases, play an important role in the hyperphosphorylation of tau (3). Candidate protein kinases include mitogen-activated protein kinase, glycogen synthase kinase-3␤, and cyclin-dependent kinase-5 (CDK5). None of these enzymes can generate PHF-tau alone (4).CDK5, initially known as brain proline-directed protein kinase or neuronal cdc2-like protein kinase, phosphorylates tau at a high stoichiometry (5, 6). Unlike other tau kinases, the activity of CDK5 is regulated by endogenous regulatory proteins, p35 and p39. In this respect, CDK5 is distinctly different from other tau kinases (7).Recently, calpain, a calcium-dependent protease, was found to digest both p35 and p39 to their truncated products, p25 and p29, respectively (8, 9). Furthermore, truncation of p35 to p25 and the subsequent formation of the p25-CDK5 complex result in neuronal cell death and hyperphosphorylation of tau (10). From these findings, the following hypothesis emerged. Initially, various stress signals activate calpain by recruiting intracellular Ca 2ϩ , and then the activated calpain digests p35 to p25. Finally, the p25-CDK5 complex hyperphosphorylates tau proteins, causing disruption of microtubule integrity and inevitable cell death (11).Several criticisms of this hypothesis have appeared. Among them, the observed accumulation of p25 in the brains of patients with Alzheimer's disease may be accounted for by postmortem degradation of p35 (12). In fact, p35 is notoriously unstable. Most brain-derived p35...

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Inhibition of tau phosphorylating protein kinase cdk5 prevents β‐amyloid‐induced neuronal death

Cited by 218 publications

References 42 publications

Tau is essential to β-amyloid-induced neurotoxicity

Tau is essential to β-amyloid-induced neurotoxicity

A 24-Residue Peptide (p5), Derived from p35, the Cdk5 Neuronal Activator, Specifically Inhibits Cdk5-p25 Hyperactivity and Tau Hyperphosphorylation

Truncation of CDK5 Activator p35 Induces Intensive Phosphorylation of Ser202/Thr205 of Human Tau

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