title: Unlocking truths of γ-secretase in Alzheimer's disease: what is the translational potential?
abstract: Considerable evidence, particularly from genetics, points to the aggregation-prone amyloid β-peptide as a pathogenic entity in Alzheimer's disease. Hence, the proteases that produce this peptide from its precursor protein have been prime targets for the development of potential therapeutics. One of these proteases, γ-secretase, has been a particular focus. Many inhibitors and modulators of this membrane-embedded protease complex have been identified, with some brought into late-stage clinical trials, where they have spectacularly failed. The reasons for these failures will be discussed, along with recent findings on the mechanism of γ-secretase and of Alzheimer-causing mutations that may suggest new strategies for targeting this enzyme.
authors.affiliation: Center for Neurologic Disease, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Tel.: +1 617 525 5511;
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolfe
keywords: amyloid; biochemistry; genetics; inhibitors; modulators; protease