The cerebral deposition of 40–42 residue amyloid β-protein (Aβ) is a characteristic of Alzheimer's disease. Cathepsin D is possibly involved in the intracellular clearance of Aβ (Hamazaki, H. (1996) FEBS Lett., in press). The present work shows that cathepsin D hydrolyzes wild-type Aβ 20 times faster than a variant Aβ with a substitution at residue 21 from Ala to Gly. Since the substitution has been linked to familial Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis (Hendriks et al. (1992) Nature Genet. 1, 218–221), the present observations suggest that the inefficient elimination of Aβ by cathepsin D is capable of being one of causes of the amyloid fibril formation.
