CDK5 and Alzheimer disease: Upon increased Ca2+ concentrations, CDK5/p25 binding is more stable, leading to the hyperphosphorylation of multiple substrates of CDK5, thus promoting AD progression.93,221 Increased phosphorylation of APP (p-Thr668) by CDK5 and excessive Aβ accumulation were observed in p25 transgenic mice222; whereas Aβ aggregation in turn contributes to abnormal CDK5 activity, forming a toxic feedback loop that aggravates AD progression.223–225