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γ-Secretase as a Target for Alzheimers Disease

[ Vol. 2 , Issue. 4 ]


Michael S. Wolf   Pages 371 - 383 ( 13 )


The amyloid-β peptide (Aβ) is the major protein component of the characteristic cerebral plaques of Alzheimers disease (AD), and a large body of evidence supports a pathogenic role for this peptide. Thus, the proteases β- and γ-secretase that are responsible for carving Ab out of its precursor protein are considered prime targets for therapeutic design. β-Secretase is a membrane-anchored aspartyl protease of the pepsin family, while γ-secretase is much more complex. γ-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 γ-secretase activity, and aspartyl protease transition-state analogue inhibitors of γ-secretase bind directly to presenilins, strong evidence that presenilin is the catalytic component of a novel membrane aspartyl protease. γ-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 γ-secretase as a target. The development of potent and selective inhibitors with good pharmacokinetic properties may soon address these concerns.




Center for NeurologicDiseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur,H.I.M. 626, Boston, Massachusetts 02115, USA

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