-Secretase as a Target for Alzheimer's Disease
Author: Wolf, M.S.
Source: Current Topics in Medicinal Chemistry, Volume 2, Number 4, 1 April 2002 , pp. 371-383(13)
Publisher: Bentham Science Publishers
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Abstract:
The amyloid-
peptide (A) 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 - and -secretase that are responsible for carving Ab out of its precursor protein are considered prime targets for therapeutic design. -Secretase is a membrane-anchored aspartyl protease of the pepsin family, while -secretase is much more complex. -Secretase requires presenilin, a multipass membrane protein that is the site of dozens of missense mutations that alter Ab formation and cause hereditary AD. Two conserved aspartates in presenilin are required for -secretase activity, and aspartyl protease transition-state analogue inhibitors of -secretase bind directly to presenilins, strong evidence that presenilin is the catalytic component of a novel membrane aspartyl protease. -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 -secretase as a target. The development of potent and selective inhibitors with good pharmacokinetic properties may soon address these concerns.
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