THE CHAPERONE BIP GRP78 BINDS TO AMYLOID PRECURSOR PROTEIN AND DECREASES A-BETA-40 AND A-BETA-42 SECRETION/

Recent studies of cellular amyloid precursor protein (APP) metabolism demonstrate a beta-/gamma-secretase pathway resident to the endoplasmi c reticulum (ER)/Golgi resulting in intracellular generation of solubl e APP (APPs beta) and A beta 42 peptide. Thus, these intracellular com partments may be key sites of amyloidogenic APP metabolism and Alzheim er's disease pathogenesis. We hypothesized that the ER chaperone immun oglobulin binding protein (BiP/GRP78) binds to and facilitates correct folding of nascent APP. Metabolic labeling and immunoprecipitation of transiently transfected human embryonic kidney 293 cells demonstrated co-precipitation of APP with GRP78, revealing their transient interac tion in the ER. Maturation of cellular APP was impaired by this intera ction. Furthermore, the levels of APPs, A beta 40, and A beta 42 recov ered in conditioned medium were lower compared with cells transfected with APP alone. Coexpression with APP of GRP78 T37G, an ATPase mutant, almost completely blocked cellular APP maturation as well as recovery of APPs, A beta 40, and A beta 42 in conditioned medium. The inhibito ry effects of GRP78 and GRP78 T37G on A beta 40 and A beta 42 secretio n mere magnified by co-expression with the Swedish mutation of APP (K6 70N/M671L). Collectively, these data suggest a transient and direct in teraction of GRP78 with APP in the ER that modulates intracellular APP maturation and processing and may facilitate its correct folding.