Cdk5 acts as a mediator of neuronal cell cycle re-entry triggered by amyloid-beta and prion peptides.
Cyclin-dependent kinase 5 (Cdk5) is a serine-threonine kinase important for different cellular processes. Involved in tau protein hyperphosphorylation and apoptotic neuronal death, two main neuropathological markers of Alzheimer's disease (AD) and Prion-related encephalopathies (PRE), Cdk5 also participates in cell cycle regulation. However, the precise relationship between cell cycle reactivation and Cdk5 dysregulation in AD and PRE remains unclear. To determine Cdk5 involvement in the triggering of an abortive cell cycle by amyloid-beta (Abeta) and prion (PrP) peptides, associated with AD and PRE pathogenesis, we examined the levels/activation of several cell cycle-associated proteins in cultured cortical neurons treated with Abeta1-40 and PrP106-126 peptides. Peptide treatments significantly increased Cdk4, phospho-retinoblastoma and proliferating cell nuclear antigen (PCNA) levels, whereas phospho-histone H3 remained invariable, suggesting cell cycle arrest before the M phase. Moreover, Abeta1-40 and PrP106-126 largely augmented the number of PCNA-immunoreactive cells with fragmented nuclei. The Cdk5 inhibitor roscovitine and the calpain inhibitor MDL28170 prevented the alterations in cell cycle markers induced by both peptides. The data obtained suggest that Abetaand PrP peptides induced neuronal cell cycle re-entry through a mechanism involving Cdk5 dysregulation. Therefore, cell cycle reactivation mediated by Cdk5 can underlie the neurodegenerative processes that occur in AD and PRE.
Lopes
João P
JP
Center for Neuroscience and Cell Biology, Faculty of Medicine, Biochemistry Institute, University of Coimbra, Coimbra, Portugal.
Oliveira
Catarina R
CR
Agostinho
Paula
P
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D002540:Cerebral Cortex / Q000166:cytology; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D016195:G2 Phase / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D008954:Models, Biological; D009410:Nerve Degeneration / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011328:Prions / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016160:Retinoblastoma Protein / Q000378:metabolism; D013997:Time Factors
D016229:Amyloid beta-Peptides; D010455:Peptides; D011328:Prions; D018809:Proliferating Cell Nuclear Antigen; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D051358:Cyclin-Dependent Kinase 4