Cdk5-p25 as a key element linking amyloid and tau pathologies in Alzheimer's disease: Mechanisms and possible therapeutic interventions
Despite the fact that the small atypical serine/threonine cyclin-dependent kinase 5 (Cdk5) is expressed in a number of tissues, its activity is restricted to the central nervous system due to the neuron-only localization of its activators p35 and p39. Although its importance for the proper developme...
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| Format: | Review |
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2023
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| Online Access: | https://repository.li.mahidol.ac.th/handle/123456789/83571 |
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| Institution: | Mahidol University |
| Summary: | Despite the fact that the small atypical serine/threonine cyclin-dependent kinase 5 (Cdk5) is expressed in a number of tissues, its activity is restricted to the central nervous system due to the neuron-only localization of its activators p35 and p39. Although its importance for the proper development and function of the brain and its role as a switch between neuronal survival and death are unmistakable and unquestionable, Cdk5 is nevertheless increasingly emerging, as supported by a large number of publications on the subject, as a therapeutic target of choice in the fight against Alzheimer's disease. Thus, its aberrant over activation via the calpain-dependent conversion of p35 into p25 is observed during the pathogenesis of the disease where it leads to the hyperphosphorylation of the β-amyloid precursor protein and tau. The present review highlights the pivotal roles of the hyperactive Cdk5-p25 complex activity in contributing to the development of Alzheimer's disease pathogenesis, with a particular emphasis on the linking function between Aβ and tau that this kinase fulfils and on the fact that Cdk5-p25 is part of a deleterious feed forward loop giving rise to a molecular machinery runaway leading to AD pathogenesis. Additionally, we discuss the advances and challenges related to the possible strategies aimed at specifically inhibiting Cdk5-p25 activity and which could lead to promising anti-AD therapeutics. |
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