PHYSICAL INTERACTION OF APOE WITH AMYLOID PRECURSOR PROTEIN INDEPENDENT OF THE AMYLOID A-BETA REGION IN-VITRO

Variation at the APOE gene locus has been shown to affect the risk for Alzheimer's disease, To gain deeper insight into the postulated apoE- mediated amyloid formation, we have characterized the three common apo E isoforms (apoE2, apoE3, and apoE4) regarding their binding to amyloi d precursor protein (APP). We employed the yeast two-hybrid system and co-immunoprecipitation experiments in cell culture supernatants of CO S-l cells, ectopically expressing apoE isoforms and APP(751) holoprote in or a COOH-terminal AP deletion mutant protein, designated APP(trunc ) We found that all three apoE isoforms were able to bind APP(751) hol oprotein in an AP-independent fashion. The interacting domains could b e mapped to the NH2 termini of APP (amino acids 1-207) and apoE (amino acids 1-191). As a functional consequence of this novel APP(751) ecto do- main-mediated apoE binding, the secretion of soluble APP(751) is d ifferentially affected by distinct apoE isoforms in vitro, suggesting a new ''chaperon-like'' mechanism by which apoE isoforms may modulate APP metabolism and consequently the risk for Alzheimer's disease.