The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation.

摘要: Hyperphosphorylation of the microtubule-associated protein tau is a characteristic feature neurodegenerative tauopathies including Alzheimer disease. Over-activation proline-directed kinases, such as cyclin-dependent kinase 5 (Cdk5) and glycogen synthase 3 (GSK3), has been implicated in aberrant phosphorylation at sites. In this study we tested roles Cdk5 GSK3 hyperphosphorylation vivo using transgenic mice with p25-induced over-activation. We found that over-activation young animals does not induce sites recognized by antibodies AT8, AT100, PHF-1, TG3. fact, observed leads to inhibition GSK3. However, old lost results increased activity, which coincides AT8 PHF-1 Pharmacological chronic treatment lithium reduction age-dependent increase hyperphosphorylation. Furthermore, Cdk5, GSK3, PP2A co-immunoprecipitate, suggesting functional association these molecules. Together, reveal role key mediator hyperphosphorylation, whereas acts modulator via inhibitory regulation findings suggest disruption activity underlies tauopathies. Hence, may be prime target for therapeutic intervention