Date of Award

8-2008

Degree Type

Thesis

Degree Name

Master of Science

Major

Comparative and Experimental Medicine

Major Professor

Xuemin Xu

Committee Members

Meizhen Cui, Hildegard Schuller, Karla Matteson

Abstract

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.

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