MilliporeSigma
  • Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology.

Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2011-12-17)
Makoto Higuchi, Nobuhisa Iwata, Yukio Matsuba, Jiro Takano, Takahiro Suemoto, Jun Maeda, Bin Ji, Maiko Ono, Matthias Staufenbiel, Tetsuya Suhara, Takaomi C Saido
ABSTRACT

The mechanism by which amyloid-β peptide (Aβ) accumulation causes neurodegeneration in Alzheimer's disease (AD) remains unresolved. Given that Aβ 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 Aβ 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 Aβ 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 Aβ 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 Aβ-triggered pathological cascade, highlighting a target for pharmacological intervention in the treatment of AD.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Growth Associated Protein-43 (GAP-43) Antibody, Chemicon®, from rabbit
Sigma-Aldrich
Anti-Glutamate receptor 1 Antibody, from rabbit, purified by affinity chromatography