Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology

The mechanism by which amyloid-beta peptide (A beta) accumulation causes neurodegeneration in Alzheimer's disease (AD) remains unresolved. Given that A beta perturbs calcium homeostasis in neurons, we investigated the possible involvement of calpain, a calcium-activated neutral protease. We first demonstrated close postsynaptic association of calpain activation with A beta plaque formation in brains from both patients with AD and transgenic (Tg) mice overexpressing amyloid precursor protein (APP). Using a viral vector-based tracer, we then showed that axonal termini were dynamically misdirected to calpain activation-positive A beta plaques. Consistently, cerebrospinal fluid from patients with AD contained a higher level of calpain-cleaved spectrin than that of controls. Genetic deficiency of calpastatin (CS), a calpain-specific inhibitor protein, augmented A beta amyloidosis, tau phosphorylation, microgliosis, and somatodendritic dystrophy, and increased mortality in APP-Tg mice. In contrast, brain-specific CS overexpression had the opposite effect. These findings implicate that calpain activation plays a pivotal role in the A beta-triggered pathological cascade, highlighting a target for pharmacological intervention in the treatment of AD.-Higuchi, M., Iwata, N., Matsuba, Y., Takano, J., Suemoto, T., Maeda, J., Ji, B., Ono, M., Staufenbiel, M., Suhara, T., Saido, T. C. Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology. FASEB J. 26, 1204-1217 (2012). www.fasebj.org