γ-Secretase as a Target for Alzheimers 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.