Open AccessProcessing of the Pre‐β‐amyloid Protein by Cathepsin d is Enhanced by a Familial Alzheimer's Disease Mutation
Author(s) -
Dreyer Robert N.,
Bausch Kathryn M.,
Fracasso Paul,
Hammond Lisa J.,
Wunderlich David,
Wirak Dana O.,
Davis Gary,
Brini Carla M.,
Buckholz Thomas M.,
König Gerhard,
Kamarck Michael E.,
Tamburini Paul P.
Publication year - 1994
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1111/j.1432-1033.1994.00265.x
Subject(s) - cathepsin d , amyloid precursor protein , cathepsin , chemistry , cathepsin b , microbiology and biotechnology , peptide bond , amyloid (mycology) , peptide , cleavage (geology) , biochemistry , alzheimer's disease , biology , enzyme , medicine , disease , inorganic chemistry , paleontology , fracture (geology)
A major pre‐β‐amyloid protein 695 (APP 695 ) processing activity from Alzheimer's disease brain extracts was identified and found to be indistinguishable from the activity of cathepsin D.APP 695 processing activity cleaved APP 695 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 APP 695 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.