title: The search for gamma-secretase and development of inhibitors.
abstract: A considerable body of evidence has accumulated in recent years implicating the beta-amyloid protein (Abeta) in the etiology of Alzheimer s disease (AD). The highly hydrophobic Abeta can nucleate and form neurotoxic fibrils that are the principal components of the cerebral plaques characteristic of AD. Abeta is formed from the amyloid-beta precursor protein (APP) through two protease activities. First, beta-secretase cleaves APP at the Abeta N-terminus, resulting in a soluble, secreted APP derivative (beta-APPs) and a 12 kDa membrane-retained C-terminal fragment. The latter is further processed to Abeta by gamma secretases, which cleave within the single transmembrane region. Other APP molecules can be cleaved by alpha-secretase within the Abeta region, thus precluding Abeta formation. Both beta- and gamma- secretase have become prime targets for the development of therapeutic agent that reduce Abeta production. Beta-secretase has recently been identified as a new membrane-anchored aspartyl protease in the cathepsin D family. Inhibitor profiling, site-directed mutagenesis, and affinity labeling together have suggested that the multi-pass presenilins are gamma-secretases, novel intramembrane-cleaving aspartyl proteases activated through autoproteolysis. In this article, we review the current knowledge of gamma-secretase biochemistry and cell biology and the development of inhibitors of this important therapeutic target.
authors.affiliation: PPG Industrial, 440 College Park Drive, Monroeville, PA 15146, USA. jytsai@ppg.com
authors.forename: Jui-Yi
authors.initials: JY
authors.lastname: Tsai
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolfe
authors.forename: Weiming
authors.initials: W
authors.lastname: Xia
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology; D018716:Molecular Mimicry; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation
chemical_list: D016564:Amyloid beta-Protein Precursor; D007769:Lactams; D010455:Peptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human