Regulation of β-amyloid secretion by FE65, an amyloid protein precursor-binding protein

The principal component of Alzheimer's amyloid plaques, A beta, derives from proteolytic processing of the Alzheimer's amyloid protein precursor (APP), FE65 is a brain-enriched protein that binds to APP, Although several laboratories have characterized the APP-FE65 interaction in vitro, the possible relevance of this interaction to Alzheimer's disease has remained unclear. We demonstrate here that APP and FE65 co-localize in the endoplasmic reticulum/Golgi and possibly in endosomes, Moreover, FE65 increases translocation of APP to the cell surface, as well as both alpha APP(s) and A beta secretion. The dramatic (4-fold) FE65-dependent increase in A beta secretion suggests that agents which inhibit the interaction of FE65 with APP might reduce A beta secretion in the brain and therefore be useful for preventing or slowing amyloid plaque formation.