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Deregulated Cdk5 causes neurotoxic Aβ processing and cell death, two hallmarks of Alzheimer's disease (AD) via FOXO3a transcriptional factor in hippocampal cells, primary neurons and an AD mouse model. Using an innovative chemical-genetic screen, we identified Foxo3a as a direct substrate of Cdk5 in brain lysates. Cdk5 directly phosphorylates FOXO3a, which increased its levels and nuclear translocation. Nuclear FOXO3a initially rescued cells from ensuing oxidative stress by upregulating MnSOD. However, following prolonged exposure, FOXO3a upregulated Bim and FasL causing cell death. Active FOXO3a also increased Aβ(1-42) levels in a phosphorylation-dependent manner. These events were completely inhibited either by expressing phosphorylation-resistant FOXO3a or by depleting Cdk5 or Foxo3, highlighting a key role of Cdk5 in regulating FOXO3a. These results were confirmed in an AD mouse model, which exhibited increased levels and nuclear localization of FOXO3a in hippocampal neurons, which preceded neurodegeneration and Aβ plaque formation, suggesting it is an early event in AD pathogenesis. These results show that Cdk5-mediated phospho-regulation of FOXO3a can activate several genes that promote neuronal death and aberrant Aβ processing, thereby contributing to the progression of neurodegenerative pathologies.

Cdk5-FOXO3a axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models