Deregulated Cdk5 triggers aberrant activation of cell cycle kinases and phosphatases inducing neuronal death.
Aberrant activation of cell cycle proteins is believed to play a critical role in Alzheimer's disease (AD) pathogenesis; although, the molecular mechanisms leading to their activation in diseased neurons remain elusive. The goal of this study was to investigate the mechanistic link between Cdk5 deregulation and cell cycle re-activation in β-amyloid(1-42) (Aβ(1-42))-induced neurotoxicity. Using a chemical genetic approach, we identified Cdc25A, Cdc25B and Cdc25C as direct Cdk5 substrates in mouse brain lysates. We show that deregulated Cdk5 directly phosphorylates Cdc25A, Cdc25B and Cdc25C at multiple sites, which not only increases their phosphatase activities but also facilitates their release from 14-3-3 inhibitory binding. Cdc25A, Cdc25B and Cdc25C in turn activate Cdk1, Cdk2 and Cdk4 kinases causing neuronal death. Selective inhibition of Cdk5 abrogates Cdc25 and Cdk activations in Aβ(1-42)-treated neurons. Similarly, phosphorylation-resistant mutants of Cdc25 isoforms at Cdk5 sites are defective in activating Cdk1, Cdk2 and Cdk4 in Aβ(1-42)-treated primary cortical neurons, emphasizing a major role of Cdk5 in the activation of Cdc25 isoforms and Cdks in AD pathogenesis. These results were further confirmed in human AD clinical samples, which had higher Cdc25A, Cdc25B and Cdc25C activities that were coincident with increased Cdk5 activity, as compared to age-matched controls. Inhibition of Cdk5 confers the highest neuroprotection against Aβ(1-42) toxicity, whereas inhibition of Cdc25 isoforms was partially neuroprotective, further emphasizing a decisive role of Cdk5 deregulation in cell-cycle-driven AD neuronal death.
Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907,  USA.
Kuei-Hua
KH
Chang
Fabien
F
Vincent
Kavita
K
Shah
D000544:Alzheimer Disease / Q000201:enzymology; D016229:Amyloid beta-Peptides / Q000502:physiology; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D051379:Mice; D009474:Neurons / Q000201:enzymology* / Q000502:physiology; D010446:Peptide Fragments / Q000502:physiology; D010766:Phosphorylation; D061251:Primary Cell Culture; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D020687:cdc25 Phosphatases / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D051360:Cyclin-Dependent Kinase 5; D016203:CDC2 Protein Kinase; C495905:CDK5 protein, human; D020687:cdc25 Phosphatases