OBJECTIVE: Glycogen synthase kinase-3beta (GSK-3beta) and cyclin-dependent kinase 5 (CDK5) have been implicated as two major protein kinases involved in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles. CDK5 regulatory subunit 1 (CDK5R1) encodes for p35, a protein required for activation of CDK5. As both CDK5R1 and GSK-3beta genes are related to phosphorylation of tau, we examined the combined contribution of these genes to the susceptibility for AD. METHODS: In a case-control study in 283 AD patients and 263 healthy controls, we examined the combined effects between CDK5R1 (3'-UTR, rs735555) and GSK-3beta (-50, rs334558) polymorphisms on susceptibility to AD. RESULTS: Subjects carrying both the CDK5R1 (3'-UTR, rs735555) AA genotype and the GSK-3beta (-50, rs334558) CC genotype had a 12.5-fold decrease in AD risk (adjusted by age, sex and APOE status OR = 0.08, 95% CI = 0.01-0.76, P = 0.03), suggesting synergistic effects (epistasis) between both genes. CONCLUSION: These data support a role for tau phosphorylation regulating genes in risk for AD.
OBJECTIVE:Glycogen synthase kinase-3beta (GSK-3beta) and cyclin-dependent kinase 5 (CDK5) have been implicated as two major protein kinases involved in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles. CDK5 regulatory subunit 1 (CDK5R1) encodes for p35, a protein required for activation of CDK5. As both CDK5R1 and GSK-3beta genes are related to phosphorylation of tau, we examined the combined contribution of these genes to the susceptibility for AD. METHODS: In a case-control study in 283 ADpatients and 263 healthy controls, we examined the combined effects between CDK5R1 (3'-UTR, rs735555) and GSK-3beta (-50, rs334558) polymorphisms on susceptibility to AD. RESULTS: Subjects carrying both the CDK5R1 (3'-UTR, rs735555) AA genotype and the GSK-3beta (-50, rs334558) CC genotype had a 12.5-fold decrease in AD risk (adjusted by age, sex and APOE status OR = 0.08, 95% CI = 0.01-0.76, P = 0.03), suggesting synergistic effects (epistasis) between both genes. CONCLUSION: These data support a role for tau phosphorylation regulating genes in risk for AD.
Authors: Juan Manuel Domínguez; Ana Fuertes; Leyre Orozco; María del Monte-Millán; Elena Delgado; Miguel Medina Journal: J Biol Chem Date: 2011-11-18 Impact factor: 5.157
Authors: Jin Li; Qiushi Zhang; Feng Chen; Jingwen Yan; Sungeun Kim; Lei Wang; Weixing Feng; Andrew J Saykin; Hong Liang; Li Shen Journal: Biomed Res Int Date: 2015-09-03 Impact factor: 3.411
Authors: Wei-na Cong; Rui Wang; Huan Cai; Caitlin M Daimon; Morten Scheibye-Knudsen; Vilhelm A Bohr; Rebecca Turkin; William H Wood; Kevin G Becker; Ruin Moaddel; Stuart Maudsley; Bronwen Martin Journal: PLoS One Date: 2013-08-07 Impact factor: 3.240