Altered processing of a mutant amyloid precursor protein in neuronal and endothelial cells.
Altered proteolysis of the amyloid precursor protein (APP) may play an important role in Alzheimer disease (AD). To better understand the role of mutant APP in the pathogenesis of the disease, we stably overexpressed the mutant APP717F approximately twofold vs. the endogenous wild-type gene in several cell types. The processing of APP was examined by Western blot analysis and immunoprecipitation. We observed distinctive patterns of APP metabolites among various cell lines. Neuronal and endothelial cells expressing mutant APP717F generated higher levels of large, potentially amyloidogenic carboxyl terminal fragments, which were enhanced upon treatment of the cells with leupeptin. These results suggest that mutations in the APP gene shift the protein processing towards the amyloidogenic pathway in neuronal and endothelial cells possibly involving the endosomal-lysosomal system.
Zhao
B
B
Molecular Neurobiology Unit/LBC, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Sisodia
S S
SS
Kusiak
J W
JW
D000544:Alzheimer Disease / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D015153:Blotting, Western; D002478:Cells, Cultured; D004727:Endothelium / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D011233:Precipitin Tests; D051381:Rats
D016564:Amyloid beta-Protein Precursor; D000906:Antibodies