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Review
. 2022 Nov 1:308:120986.
doi: 10.1016/j.lfs.2022.120986. Epub 2022 Sep 21.

Cdk5-p25 as a key element linking amyloid and tau pathologies in Alzheimer's disease: Mechanisms and possible therapeutic interventions

Subhamita Maitra  1 , Bruno Vincent  2
Affiliations
Review

Cdk5-p25 as a key element linking amyloid and tau pathologies in Alzheimer's disease: Mechanisms and possible therapeutic interventions

Subhamita Maitra et al. Life Sci. .

Abstract

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.

Keywords: Alzheimer's disease; Cdk5; Neurodegeneration; Therapeutic; p25.

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Conflict of interest statement

Declaration of competing interest None.

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