IDENTIFICATION OF 5.8-KDA C-TERMINAL FRAGMENTS OF ALZHEIMER AMYLOID-BETA PROTEIN-PRECURSOR GENERATED IN THE LYSOSOMAL SYSTEM

Elucidation of the normal metabolic pathways of amyloid beta protein precursor (A beta PP) is one of the important fields in the study of Alzheimer's disease. It has been suggested that the endosomal-lysosomal pathway may play a key role in the metabolism of A beta PP. We prepared different subcellular fractions from rat brain using a discontinuous sucrose density gradient method The lysosome-enriched fraction was identified morphologically and biochemically. Various antibodies against the C-terminus of A beta PP were employed to detect specific fragments of A beta PP in different subcellular fractions by western blot. The bands of A beta PP fragments with apparent molecular weight of 5.8 kDa, possibly containing the whole cytoplasmic domain of A beta PP, were present specifically in the lysosome-enriched fraction. The 5.8 kDa fragments were increased and full-length A beta PP was decreased during incubation of the lysosome-enriched fraction in acidic buffet: The results provided direct evidence for the degradation of A beta PP in the lysosomal system. Our data indicate that the digestion of A beta PP into these small peptides might be important in the pathogenesis of Alzheimer's disease.