Alteration of Amyloid Precursor Protein (APP) processing, leading to overproduction of Amyloid beta (Ab), and hyperphosphorylation of Microtubule-Associated Protein (MAP) tau remain in the center of pathomechanism of Alzheimer’s disease (AD). The recent data indicated that oligomeric form of Aβ is responsible for memory impairment in AD. Also deregulation of protein phosphorylation processes plays an important role in AD pathology. Cyclin-Dependent Kinase 5 (CDK5) is responsible for aberrant phosphorylation of both MAP tau and APP. Moreover, CDK5 may also phosphorylate other proteins potentially involved in AD pathogenesis, i.a. Glycogen Synthase Kinase-3b (GSK-3b), NMDAR, p53. The aim of the present study was to analyze the participation of CDK5 in cell death processes occurring in PC12 cells overexpressing APP. As a model, we used cells transfected with human wild-type APP (APPwt) and human APP with Swedish mutation (APPsw). Real-time PCR and Western blotting were used for analysis of expression and phosphorylation of CDK5, CDK5R1, CDK5R2, GSK-3β. Cytotoxicity was evaluated by MTT and LDH tests. To determine the role of CDK5 in AD patients, the association of human CDK5 gene with AD risk was analyzed. Our data demonstrated enhanced cell death and cell cycle disturbances in PC12 cells transfected with APP gene, comparing to control PC12 cells. Real-time PCR analysis indicated increased level of mRNA for CDK5 gene in APPsw cells. Significantly decreased phosphorylation of CDK5 on Tyr15 was observed in APPwt and APPsw cells, what can be responsible for lowering of Cdk5 activity. Moreover, Cdk5-dependent phosphorylation of GSK-3β on Ser9 was also decreased, what can be responsible for GSK-3β activation, hyperphosphorylation of MAP tau and alteration of cell function. Our genetic analysis indicated that there is no association between polymorphism of CDK5 gene and the risk of AD in investigated Polish population (178 healthy controls, 71 EOAD and 204 LOAD cases). Significant differences in serum level of cholesterol, LDL, vitamin B12 and homocysteine between AD patients and healthy controls were found, but there was no association of tested CDK5 genotypes with biochemical parameters. These results indicated the important role of CDK5 - GSK-3β interplay in pathomechanism of AD. This study was supported by MSHE Grant N N401 014635
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