The Reduction of Tau Hyperphosphorylation by Cornel Iridoid Glycosides Is Mediated by Their Influence on Calpain Activity

Alzheimer's disease (AD) is the most common type of dementia, and the abnormal hyperphosphorylation of the tau protein is the main component of its pathogenesis. Calpain was found to be abnormally activated in neurofibrillary tangles (NFTs) in a previous report. Cornel iridoid glycosides (CIG) have been reported to reduce the hyperphosphorylation of tau protein. Nevertheless, the role of calpain in the reduction tau hyperphosphorylation by CIG remains unclear. In the present study, we investigated the effect of CIG on calpain activity through in vitro and in vivo experiments. Western blotting results suggested that CIG decreased the phosphorylation of tau at Ser 404 and Ser 262 sites in P301S mice. Moreover, CIG inhibited the activity of calpain and glycogen synthase kinase 3β (GSK-3β) and enhanced the activity of protein phosphatase 2A (PP2A) both in vivo and in vitro. CIG also inhibited the activation of PP2A and reduced the GSK-3β activity caused by the calpain activator dibucaine. In addition, the main components of CIG, morroniside and loganin, play an equivalent role in reducing calpain activity, as the effect of their combined use is equivalent to that of CIG. The abovementioned findings revealed that CIG improved PP2A activity and reduced GSK-3β activity by adjusting the activity of calpain 1, leading to a reduction in the phosphorylation of tau. This study highlights the remarkable therapeutic potential of CIG for managing AD.