Hyperphosphorylated tan and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5

Hyperphosphorylation of microtubule-associated proteins such as tau and neu rofilament may underlie the cytoskeletal abnormalities and neuronal death s een in several neurodegenerative diseases including Alzheimer's disease. On e potential mechanism of microtubule-associated protein hyperphosphorylatio n is augmented activity of protein kinases known to associate with microtub ules, such as cdk5 or GSK3 beta, Here we show that tau and neurofilament ar e hyperphosphorylated in transgenic mice that overexpress human p25, an act ivator of cdk5. The p25 transgenic mice display silver-positive neurons usi ng the Bielschowsky stain. Disturbances in neuronal cytoskeletal organizati on are apparent at the ultrastructural level. These changes are localized p redominantly to the amygdala, thalamus/hypothalamus, and cortex. The p25 tr ansgenic mice display increased spontaneous locomotor activity and differen ces from control in the elevated plus-maze test. The overexpression of an a ctivator of cdk5 in transgenic mice results in increased cdk5 activity that is sufficient to produce hyperphosphorylation of tau and neurofilament as well as cytoskeletal disruptions reminiscent of Alzheimer's disease and oth er neurodegenerative diseases.