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Volume 271, Number 44, Issue of November 1, 1996 pp. 27241-27244
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Amyloidogenic Processing of Human Amyloid Precursor Protein in Hippocampal Neurons Devoid of Cathepsin D

(Received for publication, June 13, 1996, and in revised form, August 16, 1996)

Paul Saftig , Christoph Peters , Kurt von Figura , Katleen Craessaerts ^§ , Fred Van Leuven ^§ and Bart De Strooper ^§

From  Zentrum Biochemie und Molekular Zellbiologie, Abteilung Biochemie II, Universität Göttingen, Goßlerstraße 12D, 37073 Göttingen, Germany and the ^§ Experimental Genetics Group, Center for Human Genetics, UZ Gasthuisberg, O&N 6, 3000 Leuven, Belgium

A4-Amyloid peptide, the main component of the amyloid plaques in the brain of Alzheimer's disease patients is produced from amyloid precursor protein (APP) by proteolytical processing. Several lines of evidence suggest a direct role for cathepsin D, the major endosomal/lysosomal aspartic endopeptidase, in A4-amyloid peptide generation. Here we tested this hypothesis using primary cultures of hippocampal neurons derived from cathepsin D-deficient (knock out) mice and expressing wild-type human APP and two clinical APP variants via recombinant Semliki Forest virus. We demonstrate APP secretory processing, production of carboxyl-terminal amyloid fragments, and secretion of the A4-amyloid peptide in the complete absence of cathepsin D. The results rule out cathepsin D as a critical component of -, -, or -secretase and therefore as a primary target for drugs aimed at decreasing the A4-amyloid peptide burden in Alzheimer's disease.

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