Cdk5-Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models.
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.
Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA.
Chun
0000-0001-6391-9100
C
Shi
Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA.
Keith
K
Viccaro
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.
Hyoung-Gon
HG
Lee
Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA shah23@purdue.edu.
Kavita
0000-0002-0451-1305
K
Shah
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D016229:Amyloid beta-Peptides; D000072224:Bcl-2-Like Protein 11; D051360:Cyclin-Dependent Kinase 5; D000071316:Forkhead Box Protein O3; D010446:Peptide Fragments; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C000606776:Bcl2l11 protein, mouse; C474033:FoxO3 protein, mouse; C075222:amyloid beta-protein (1-42); C495906:Cdk5 protein, mouse
Alzheimer's disease; Cdk5; Foxo3; Neurodegeneration; Neuroprotection