Targeting Calpain-2 for Alzheimer’s Disease Treatment

There is an urgent need for treatments sporadic Alzheimer’s Disease (sAD). Although antibodies removing ß-amyloid have recently been shown to slow disease progression, the degenerative course continues. Thus, there a strategies that intervene early in process, before irreversible damage done neurons (e.g., by autophagic degeneration). This review will summarize evidence indicating targeting calpain-2 with selective inhibitor might represent novel strategy treatment of sAD. Calpains are neutral proteases activated intracellular calcium. The two main isoforms calpain-1, which low, micromolar levels calcium and generally has beneficial effects cellular health, calpain-2, high, almost millimolar mediates many calcium’s toxic actions. Calcium signaling becomes dysregulated advancing age due loss regulatory proteins such as calbindin, pronounced sAD brain tissue, including signs leakage from smooth endoplasmic reticulum (SER) through phosphorylated ryanodine receptors (pRyR2). Both calpain-1 elevated AD brains herald rise tau pathology, but only localized neurofibrillary tangles (NFTs) pretangles. Calpain drives spectrum AD-related pathologies, particular, calpain hyperphosphorylation cleaving, thus disinhibiting, kinases central hyperphosphorylation, i.e., GSK3β cdk5, well increasing Aβ formation degeneration. Thus inhibitors may reduce protecting at very stages disease.