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  • PMID: 26962010 was deleted because it is a duplicate of PMID: 28157684
J Cell Sci. 2016 May 1;129(9):1815-1830. doi: 10.1242/jcs.185009. Epub 2016 Mar 9.

Cdk5-Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models.

Author information

1
Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA.
2
Department of Pathology, Case Western Reserve University School of Medicine, Iris S. Bert L. Wolstein Research Building, 2103 Cornell Road, Room 5123, Cleveland, OH 44106, USA.
3
Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA shah23@purdue.edu.

Abstract

Deregulated Cdk5 causes neurotoxic amyloid beta peptide (Aβ) processing and cell death, two hallmarks of Alzheimer's disease, through the Foxo3 transcriptional factor in hippocampal cells, primary neurons and an Alzheimer's disease mouse model. Using an innovative chemical genetic screen, we identified Foxo3 as a direct substrate of Cdk5 in brain lysates. Cdk5 directly phosphorylates Foxo3, which increased its levels and nuclear translocation. Nuclear Foxo3 initially rescued cells from ensuing oxidative stress by upregulating MnSOD (also known as SOD2). However, following prolonged exposure, Foxo3 upregulated Bim (also known as BCL2L11) and FasL (also known as FASLG) causing cell death. Active Foxo3 also increased Aβ(1-42) levels in a phosphorylation-dependent manner. These events were completely inhibited either by expressing phosphorylation-resistant Foxo3 or by depleting Cdk5 or Foxo3, highlighting a key role for Cdk5 in regulating Foxo3. These results were confirmed in an Alzheimer's disease mouse model, which exhibited increased levels and nuclear localization of Foxo3 in hippocampal neurons, which preceded neurodegeneration and Aβ plaque formation, indicating this phenomenon is an early event in Alzheimer's disease pathogenesis. Collectively, these results show that Cdk5-mediated phospho-regulation of Foxo3 can activate several genes that promote neuronal death and aberrant Aβ processing, thereby contributing to the progression of neurodegenerative pathologies.

KEYWORDS:

Alzheimer's disease; Cdk5; Foxo3; Neurodegeneration; Neuroprotection

PMID:
28157684
PMCID:
PMC4893801
DOI:
10.1242/jcs.185009
[Indexed for MEDLINE]

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