The calpain-mediated proteolytic cleavage peptide P10 modulates Tau phosphorylation in Alzheimer's disease.

Alzheimer's disease is a prominent neurological disorder, which leads to progressive dementia. The microtubule-associated protein Tau is considered one of the major causes of Alzheimer's disease. Hyper-phosphorylation of Tau is considered to be closely associated with the generation of Tau pathology. CDK5 is one of the prominent neuronal kinases, under normal conditions, the activity of CDK5 is regulated by p35 protein. The stress conditions result in calpain-mediated proteolytic cleavage of p35 leading to the generation of p25 and p10. CDK5/p25 complex is reported to have a relatively more half-life which causes hyperphosphorylation of many proteins leading to neurotoxicity but the role of p10 is still needed to be explored. In the present review, we hypothesized the role of p10 as CDK5/p25 inhibitor. The current research has demonstrated that p10 provides survival signals to cells. In the current scenario, several CDK5 inhibitors commonly have a drawback of non-specificity. Here based on complied studies we hypothesize that the p10 could have the potency to inhibit the activity of CDK5, which ultimately downregulate the hyperphosphorylation of Tau. Thus reducing the levels of phospho-Tau p10 could emerge as a novel therapeutic peptide against Alzheimer's disease. The proposed hypothesis would open new gates for research in the field of Alzheimer's and further would bring a new ray of hope for the disease.