The Chaperone BiP/GRP78 Binds to Amyloid Precursor Protein and Decreases Aβ40 and Aβ42 Secretion

Abstract

Recent studies of cellular amyloid precursor protein (APP) metabolism demonstrate a ␤-/␥-secretase pathway resident to the endoplasmic reticulum (ER)/Golgi resulting in intracellular generation of soluble APP (APPs␤) and A␤42 peptide. Thus, these intracellular compartments may be key sites of amyloidogenic APP metabolism and Alzheimer's disease pathogenesis. We hypothesized that the ER chaperone immunoglobulin 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 interaction in the ER. Maturation of cellular APP was impaired by this interaction. Furthermore, the levels of APPs, A␤40, and A␤42 recovered 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␤40, and A␤42 in conditioned medium. The inhibitory effects of GRP78 and GRP78 T37G on A␤40 and A␤42 secretion were magnified by co-expression with the Swedish mutation of APP (K670N/M671L). Collectively, these data suggest a transient and direct interaction of GRP78 with APP in the ER that modulates intracellular APP maturation and processing and may facilitate its correct folding.The major components of amyloid plaque in Alzheimer's disease (AD) 1 brain are A␤ peptides, including A␤40 and A␤42, that are derived from amyloid precursor protein (APP). APP is metabolized at or near the cell surface by an ␣-secretase that results in soluble APP (APPs␣) secretion and precludes A␤ formation. APP is also metabolized by an endosomal/lysosomal (endocytic) pathway that results in A␤ secretion (1-3). Recent data with human NT2 neurons demonstrates that A␤ is found intracellularly (4) with kinetics identical to APP synthesis, suggesting that a fraction of nascent APP is immediately metabolized to A␤ (5). Subsequently, a ␤-/␥-secretase pathway of APP metabolism resident to the endoplasmic reticulum (ER)/ Golgi of neurons was identified, resulting in intracellular APPs␤ and A␤42 generation (6 -11). This exocytic pathway may be specifically promoted by presenilin-1 and presenilin-2 mutations found in some pedigrees of familial AD, since these proteins localize to the ER/Golgi (12-14) and result in greater A␤42 secretion (15-17). In fact, common to all mutations of APP and presenilins linked to early-onset familial AD is their ability to promote A␤42 generation (1-3). Because A␤42 is intrinsically more amyloidogenic than A␤40 and deposits preferentially in brain, this relatively minor pathway of APP metabolism within the ER/Golgi may have major implications for AD pathogenesis. All proteins destined for the cell membrane or secretion must first translocate into the ER. Newly translocated proteins are folded and assembled by a group of proteins, which include immunoglobulin-binding protein (BiP)/glucose-regulated...

Endoplasmic Reticulum Stress and Unfolded Protein Response in Inclusion Body Myositis Muscle

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