Processing of the Pre‐β‐amyloid Protein by Cathepsin d is Enhanced by a Familial Alzheimer's Disease Mutation
Open Access
- 1 September 1994
- journal article
- Published by Wiley in European Journal of Biochemistry
- Vol. 224 (2) , 265-271
- https://doi.org/10.1111/j.1432-1033.1994.00265.x
Abstract
A major pre-β-amyloid protein695 (APP695) processing activity from Alzheimer's disease brain extracts was identified and found to be indistinguishable from the activity of cathepsin D.APP695 processing activity cleaved APP695 into a series of fragments that reacted on immunoblots to a monoclonal antibody (C286.8a) against β-amyloid-(1–7)-peptide and cleaved N -dansyl-APP-(591–601)-amide at the Glu-Val and Met-Asp bonds. Fragments of 5.5 kDa and 10–12 kDa were formed from the cleavage of APP695 by cathepsin D at the Glu593-Va1594 bond, and had the same N-terminus as a minor form of β-amyloid released by cells. The Lys595→Asn and Met596→Leu substitutions found in a pedigree of familial Alzheimer's disease, increased the cathepsin d-catalyzed rate of accumulation of 5.5 kDa and 10–12 kDa C286.8a-reactive fragments 5–10fold. This substitution also increased the rate of N-dansyl-APP-(591–601)-amide cleavage at the Xaa-Asp bond by up to 41-fold. These observations suggest a role of cathepsin D in β-amyloid formation under certain circumstances.Keywords
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