AMYLOIDOGENIC PROCESSING OF HUMAN AMYLOID PRECURSOR PROTEIN IN HIPPOCAMPAL-NEURONS DEVOID OF CATHEPSIN-D

beta A4-Amyloid peptide, the main component of the amyloid plaques in the brain of Alzheimer's disease patients is produced from amyloid pre cursor protein (APP) by proteolytical processing. Several lines of evi dence suggest a direct role for cathepsin D, the major endosomal/lysos omal aspartic endopeptidase, in beta A4-amyloid peptide generation, He re we tested this hypothesis using primary cultures of hippocampal neu rons derived from cathepsin D-deficient (knock out) mice and expressin g wild-type human APP and two clinical APP variants via recombinant Se mliki Forest virus. We demonstrate APP secretory processing, productio n of carboxyl-terminal amyloid fragments, and secretion of the beta A4 -amyloid peptide in the complete absence of cathepsin D. The results r ule out cathepsin D as a critical component of alpha-, beta-, or gamma -secretase and therefore as a primary target for drugs aimed at decrea sing the beta A4-amyloid peptide burden in Alzheimer's disease.