Secretase as a target for Alzheimer's disease.
The amyloid-beta peptide (Abeta) is the major protein component of the characteristic cerebral plaques of Alzheimer s disease (AD), and a large body of evidence supports a pathogenic role for this peptide. Thus, the proteases beta- and gamma-secretase that are responsible for carving Abeta out of its precursor protein are considered prime targets for therapeutic design. beta-Secretase is a membrane-anchored aspartyl protease of the pepsin family, while gamma-secretase is much more complex. gamma-Secretase requires presenilin, a multipass membrane protein that is the site of dozens of missense mutations that alter Abeta formation and cause hereditary AD. Two conserved aspartates in presenilin are required for gamma-secretase activity, and aspartyl protease transition-state analogue inhibitors of gamma-secretase bind directly to presenilins, strong evidence that presenilin is the catalytic component of a novel membrane aspartyl protease. gamma-Secretase appears to be a multi-component complex of integral membrane proteins, and so far presenilin and a single-pass membrane protein called nicastrin have been identified as members of this complex. A closely similar or identical protease activity is essential for a signaling pathway critical for embryogenesis and hematopoiesis, raising concerns about gamma-secretase as a target. The development of potent and selective inhibitors with good pharmacokinetic properties may soon address these concerns.
Wolfe
Michael S
MS
Center for Neurologic Diseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, H.I.M. 626, Boston, MA 02115, USA. mwolfe@rics.bwh.harvard.edu
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D015335:Molecular Probes; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors / Q000627:therapeutic use*
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D015335:Molecular Probes; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human