Candidate γ-Secretases in the Generation of the Carboxyl Terminus of the Alzheimer's Disease βA4 Amyloid: Possible Involvement of Cathepsin D

Abstract

βA4 amyloid peptide, the main constituent of amyloid plaques and cerebrovascular amyloid deposits associated with Alzheimer's disease, derives from a large precursor protein (APP) by the action of β- and γ-secretases, the unidentified endoproteases which release the amino and carboxyl termini of βA4, respectively. Several γ-secretase cleavage sites exist which yield the more soluble (1-39/40) forms of βA4 and the longer forms (1-42/43) which have a greater tendency to aggregate into amyloid plaques. γ-Secretase activity may therefore be critical in amyloid formation. In this study, a synthetic peptide which encompasses the various γ-secretase cleavage sites was used as a substrate to probe p..