Endosomal sorting of amyloid precursor protein-P-selectin chimeras influences secretase processing

Amyloid beta protein, the major component of the senile plaques in Alzheime r's disease, is generated by secretory and endocytic processing of amyloid precursor protein. Internalized amyloid precursor protein either recycles t o the plasma membrane, where alpha -secretase resides, or moves to acidic c ompartment(s) for beta -secretase exposure. While the trans-Golgi network c ontains beta -secretase activity, recent examination of the subcellular dis tribution of this proteinase, called BACE, has led to the suggestion that b eta -secretase activity might also reside at the plasma membrane and in end osomes. To examine the role of endocytic compartments in beta -secretase pr ocessing of amyloid precursor protein, the wild-type and endosomal sorting mutant P-selectin cytoplasmic domains were used to control movement of amyl oid precursor protein through endosomes. Amyloid precursor protein/P-select in, which is sorted from early to late endosomes, undergoes significantly l ess a-secretase cleavage, and more beta -secretase cleavage, than amyloid p recursor protein/P-selectin768A, a mutant that recycles more efficiently to the cell surface. Our results demonstrate that endosomal sorting influence s relative exposure of the amyloid precursor protein/P-selectin chimeras to alpha- and beta -secretase activities, and suggest that, because delivery to late endocytic compartments favors beta -secretase processing of amyloid precursor protein, there is likely limited beta -secretase activity in ear ly endosomes or at the cell surface. We propose that the trans-Golgi networ k may be involved in both secretory and endocytic generation of amyloid bet a protein.