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Deregulated Cdk5 triggers aberrant activation of cell cycle kinases and phosphatases inducing neuronal death

Kuei-Hua Chang1, Fabien Vincent, Kavita Shah

  • 1Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.

Journal of Cell Science
|August 18, 2012
PubMed

Insights

Deregulation of Cdk5 kinase in Alzheimer's disease (AD) activates Cdc25 phosphatases, leading to cell cycle re-entry and neuronal death. Inhibiting Cdk5 offers significant neuroprotection against amyloid-beta toxicity in AD.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Aberrant cell cycle protein activation is implicated in Alzheimer's disease (AD) pathogenesis.
  • The precise molecular mechanisms driving this activation in diseased neurons are not fully understood.

Purpose of the Study:

  • To investigate the mechanistic link between Cyclin-dependent kinase 5 (Cdk5) deregulation and cell cycle re-activation in beta-amyloid (Aβ(1-42))-induced neurotoxicity.
  • To elucidate the role of Cdk5 in the activation of Cdc25 phosphatases and subsequent cyclin-dependent kinases (Cdks) in AD.

Main Methods:

  • Utilized a chemical genetic approach in mouse brain lysates and primary cortical neurons.
  • Identified direct Cdk5 substrates and analyzed their phosphatase activities.
  • Employed phosphorylation-resistant mutants to assess the functional significance of Cdk5 phosphorylation sites.
  • Examined human AD clinical samples for protein activities and compared them to age-matched controls.

Main Results:

  • Cdc25A, Cdc25B, and Cdc25C were identified as direct Cdk5 substrates.
  • Deregulated Cdk5 phosphorylates Cdc25 isoforms, increasing their activity and facilitating release from 14-3-3 inhibition.
  • Activated Cdc25 phosphatases subsequently activate Cdk1, Cdk2, and Cdk4, leading to neurotoxicity.
  • Selective Cdk5 inhibition prevented Cdc25 and Cdk activation in Aβ(1-42)-treated neurons.
  • Human AD samples showed elevated Cdc25 and Cdk5 activities compared to controls.
  • Cdk5 inhibition provided the highest neuroprotection against Aβ(1-42) toxicity.

Conclusions:

  • Cdk5 deregulation plays a critical role in activating Cdc25 phosphatases and Cdks, driving cell-cycle re-entry and neuronal death in Alzheimer's disease.
  • Targeting Cdk5 offers a promising therapeutic strategy for mitigating Aβ(1-42)-induced neurotoxicity in AD.

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