DELETION OF AN ENDOSOMAL LYSOSOMAL TARGETING SIGNAL PROMOTES THE SECRETION OF ALZHEIMERS-DISEASE AMYLOID PRECURSOR PROTEIN (APP)/

Alzheimer's disease amyloid precursor protein (APP) generates a beta-a myloid protein (A beta) that is a main component of the senile plaques found in the brains of Alzheimer's disease patients, APP is thought t o undergo proteolysis via two different pathways, the amyloidogenic pa thway which produces Ap, and the non-amyloidogenic pathway which relea ses a large N-terminal fragment into the medium, The proteases that me diate these processes remain unidentified, The physiological function of APP is not clear yet, Therefore, the cytoplasmic region of APP has attracted much interest, because this region is highly conserved among species, and members of the amyloid precursor-like protein (APLP) fam ily, Several potentially functional sequences exist in the region, inc luding signal sequences for protein sorting and a G(0)-protein binding sequence, We constructed two mutants, 695 Delta NPTY and 695 Delta GY EN. They lack potential endosome/lysosome targeting signals, NPTY and GY, in the cytoplasmic domain of APP695, respectively, The mutant APPs had longer half-lives and were secreted more easily into the medium t han the wild type, suggesting that these sequences are important for t he secretion and metabolism of APP.