Endosomal sorting of amyloid precursor protein-P-selectin chimeras influences secretase processing.
Amyloid beta protein, the major component of the senile plaques in Alzheimer's disease, is generated by secretory and endocytic processing of amyloid precursor protein. Internalized amyloid precursor protein either recycles to the plasma membrane, where alpha-secretase resides, or moves to acidic compartment(s) for beta-secretase exposure. While the trans-Golgi network contains beta-secretase activity, recent examination of the subcellular distribution of this proteinase, called BACE, has led to the suggestion that beta-secretase activity might also reside at the plasma membrane and in endosomes. To examine the role of endocytic compartments in beta-secretase processing of amyloid precursor protein, the wild-type and endosomal sorting mutant P-selectin cytoplasmic domains were used to control movement of amyloid precursor protein through endosomes. Amyloid precursor protein/P-selectin, which is sorted from early to late endosomes, undergoes significantly less alpha-secretase cleavage, and more beta-secretase cleavage, than amyloid precursor protein/P-selectin768A, a mutant that recycles more efficiently to the cell surface. Our results demonstrate that endosomal sorting influences 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 early endosomes or at the cell surface. We propose that the trans-Golgi network may be involved in both secretory and endocytic generation of amyloid beta protein.
Daugherty
B L
BL
Department of Cell Biology, University of Virginia Health System, School of Medicine, PO Box 800732, Charlottesville, VA 22908-0732, USA.
Green
S A
SA
D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D016466:CHO Cells; D006224:Cricetinae; D004705:Endocytosis; D010450:Endopeptidases / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D019007:P-Selectin; D011993:Recombinant Fusion Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human