P25: A hidden target for AD therapeutic.

Alzheimer's disease (AD) is an irreversible, progressive brain disorder that is characterized by dementia. Amounts of p25 and cdk5 kinase activity are specifically upregulated in AD patient's brain samples. Considerable evidence now points importance of p25/cdk5 in generation of A$\beta$ peptides and hyperphosphorylation of tau linking amyloid plaques and neurofibrillary tangles, two major pathological hallmarks of AD. We demonstrated that P25/CDK5 phosphorylates BACE1, the first step protease to produce A$\beta$. P25/CDK5 inhibitors to reduce BACE1 phosphorylation and the secretion of A$\beta$ are screened through in silica, in vitro, and cell-based assays. Out of 4.3 million chemicals we finally selected two compounds to have IC50 of 10 microM in cell-based assays. The inhibitors block Tau phosphrorylation as well as BACE1 phosphorylation. In conclusion P25 should be one of the best targets for AD therapeutics.