The Effects of Calpain on the Degradation of Amyloid Beta (Aβ) Protein

Abnormal accumulation of amyloid beta-peptide (A-beta) is believed to be the primary event in the pathogenesis of Alzheimer’s disease (AD). Two cellular mechanisms could contribute to the abnormal accumulation of Aβ in the brain: over production and/or failure in clearance of this A-beta peptide. In an effort to identify the cellular system that is involved in A-beta clearance, we conducted experiments to investigate the effects of calpain inhibitors on the production of secreted A-beta and the intracellular accumulated derivatives of APP, using a culture cell model. Our results revealed that at low concentration, calpain inhibitors caused an increase in the accumulation of both A-beta 40 and A-beta 42. At high concentration, calpain inhibitors led to a decline in A-beta accumulation toward the basal level and an increase in intracellular accumulation of C-terminal fragments, including CTF-beta, CTF-alpha, generated by beta– and alpha-cleavage, respectively. These results suggest that calpain enzymes, which are a highly conserved superfamily of calcium dependent papain-like cysteine proteases, are involved in the metabolism of APP and the formation and accumulation of A-beta. To further identify the enzyme(s) that is responsible for calpain inhibitor-regulated A-beta formation and accumulation, we employed the small interference RNA (siRNA) approach to investigate the effect of knockdown of calpains on the formation and accumulation of A-beta. Our results suggest that different isoforms of calpain enzymes may function differently in A-beta production and accumulation. This information may lead to a better understanding of the mechanism underlying the abnormal accumulation of A-beta peptide in the Alzheimer’s disease brain and provide new insight into the pathogenesis of this disease.