Cdk5 as a drug target for the treatment of Alzheimer's disease.
Cyclin-dependent kinase-5 (cdk5) is suggested to play a role in tau phosphorylation and contribute to the pathogenesis of Alzheimer's disease (AD). One of its activators, p25, is dramatically increased in AD brains where p25 and cdk5 are colocalized with neurofibrillary tangles. Several animal models have shown a correlation of p25/cdk5 activities with tau phosphorylation. Overexpression of p25/cdk5 in nueronal cultures not only leads to tau phosphorylation but also cytoskeletal abnormalities and neurodegeneration. Therefore, cdk5 kinase inhibitors are potential therapeutic agents for the treatment of AD. Availability of potent, selective, brain permeable cdk5 inhibitors and relevant animal models in which their efficacy can be treated will be critical in the development of these inhibitors.
Lau
Lit-Fui
LF
CNS Discovery, Pfizer Global Research and Development, Groton, CT 06340, USA. lit-fui_lau@groton.pfizer.com
Seymour
Patricia A
PA
Sanner
Mark A
MA
Schachter
Joel B
JB
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D000818:Animals; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases