APP, Notch, and presenilin: molecular pieces in the puzzle of Alzheimer's disease.
Deposition of the amyloid-beta protein (Abeta) in the form of cerebral plaques is a defining pathological feature of Alzheimer's disease (AD), and all AD-causing genes identified to date affect Abeta production or deposition. For these reasons, the two proteases, beta- and gamma-secretases, that cut out Abeta from the amyloid-beta precursor protein (APP) are considered important targets for the development of therapeutics for AD. AD-causing mutations in the presenilin genes alter y-secretase activity, increasing production of the more deleterious 42-residue form of Abeta. Pharmacological profiling, site-directed mutagenesis, knockout studies, affinity labeling, and activity-dependent chromatography all strongly support the hypothesis that presenilin is an integral component of gamma-secretase, a founding member of an emerging class of polytopic membrane proteases. Gamma-Secretase/ presenilin also cleaves other proteins that are important for critical signaling events (the Notch family of receptors), raising concerns about mechanism-based toxicities that might arise as a consequence of inhibiting this protease. In light of these findings, the potential of gamma-secretase vis-à-vis beta-secretase as therapeutic targets for the prevention or treatment of AD will be discussed.
Wolfe
Michael S
MS
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, H.I.M. 626, Boston, MA 02115, USA. mwolfe@rics.bwh.harvard.edu
D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D053764:Presenilin-1; D011480:Protease Inhibitors / Q000627:therapeutic use; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human