Presenilin, Notch, and the genesis and treatment of Alzheimer's disease.
Elucidation of the proteolytic processing of the amyloid beta-protein precursor (APP) has revealed that one of the two proteases (gamma-secretase) that cleave APP to release amyloid beta-protein (Abeta) is likely to be presenilin. Presenilin also mediates the gamma-secretase-like cleavage of Notch receptors to enable signaling by their cytoplasmic domains. Therefore, APP and Notch may be the first identified substrates of a unique intramembranous aspartyl protease that has presenilin as its active-site component. In view of the evidence for a central role of cerebral build-up of Abeta in the pathogenesis of Alzheimer's disease, this disorder appears to have arisen in the human population as a late-life consequence of the conservation of a critical developmental pathway.
Selkoe
D J
DJ
Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM 730, Boston, MA 02115, USA. selkoe@cnd.bwh.harvard.edu
D000544:Alzheimer Disease / Q000503:physiopathology* / Q000628:therapy*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D053764:Presenilin-1; D053766:Presenilin-2
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human