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

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

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.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Amyloid beta-Protein Precursor / metabolism
  • Amyloidosis*
  • Calpain / metabolism
  • Cyclin-Dependent Kinase 5 / metabolism
  • Humans
  • Phosphorylation
  • Serine / metabolism
  • Threonine / metabolism
  • Threonine / therapeutic use
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • tau Proteins
  • Threonine
  • Serine
  • Cyclin-Dependent Kinase 5
  • CDK5 protein, human
  • Calpain