Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration

Cyclin-dependent kinase 5 (Cdk5) is required for proper development of the mammalian central nervous system. To be activated, Cdk5 has to associate wi th its regulatory subunit, p35, We have found that p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's dis ease. This accumulation correlates with an increase in Cdk5 kinase activity . Unlike p35, p25 is not readily degraded, and binding of p25 to Cdk5 const itutively activates Cdk5, changes its cellular location and alters its subs trate specificity, In vivo the p25/Cdk5 complex hyperphosphorylates tau, wh ich reduces tau's ability to associate with microtubules, Moreover, express ion of the p25/Cdk5 complex in cultured primary neurons induces cytoskeleta l disruption, morphological degeneration and apoptosis, These findings indi cate that cleavage of p35, followed by accumulation of p25, may be involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in ne urodegenerative diseases.