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.