Neurodegeneration in an Abeta-induced model of Alzheimer's disease: the role of Cdk5.
Cdk5 dysregulation is a major event in the neurodegenerative process of Alzheimer's disease (AD). In vitro studies using differentiated neurons exposed to Abeta exhibit Cdk5-mediated tau hyperphosphorylation, cell cycle re-entry and neuronal loss. In this study we aimed to determine the role of Cdk5 in neuronal injury occurring in an AD mouse model obtained through the intracerebroventricular (icv) injection of the Abeta(1-40) synthetic peptide. In mice icv-injected with Abeta, Cdk5 activator p35 is cleaved by calpains, leading to p25 formation and Cdk5 overactivation. Subsequently, there was an increase in tau hyperphosphorylation, as well as decreased levels of synaptic markers. Cell cycle reactivation and a significant neuronal loss were also observed. These neurotoxic events in Abeta-injected mice were prevented by blocking calpain activation with MDL28170, which was administered intraperitoneally (ip). As MDL prevents p35 cleavage and subsequent Cdk5 overactivation, it is likely that this kinase is involved in tau hyperphosphorylation, cell cycle re-entry, synaptic loss and neuronal death triggered by Abeta. Altogether, these data demonstrate that Cdk5 plays a pivotal role in tau phosphorylation, cell cycle induction, synaptotoxicity, and apoptotic death in postmitotic neurons exposed to Abeta peptides in vivo, acting as a link between diverse neurotoxic pathways of AD.
Lopes
Joao P
JP
Center for Neuroscience and Cell Biology, Faculty of Medicine, Biochemistry Institute, University of Coimbra, 3004 Coimbra, Portugal.
Oliveira
Catarina R
CR
Agostinho
Paula
P
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D002455:Cell Division; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D016195:G2 Phase; D015552:Injections, Intralesional; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000378:metabolism* / Q000517:prevention & control; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011480:Protease Inhibitors / Q000008:administration & dosage; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004151:Dipeptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; C078592:amyloid beta-protein (1-40); D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D002154:Calpain; C058076:calpain inhibitor III