gamma-Secretase structure and activity are modified by alterations in its membrane localization and ambient environment

gamma-Secretase cleaves type I transmembrane proteins in a hydrophobic membrane environment following ectodomain shedding. Mutations in PSEN genes, encoding the catalytic subunits of gamma-secretase, presenilins, are the most common cause of familial Alzheimer's disease (ad). Pathogenic mutations in PSEN genes increase production of longer and neurotoxic amyloid-beta (A beta) by intramembrane cleavage of membrane-associated amyloid-beta protein precursor (APP) carboxyl-terminal fragment beta, which is generated via primary cleavage of APP by beta-site APP cleaving enzyme 1. The longer A beta is prone to aggregate and accumulate in the brain; however, the accumulation of A beta in brain is also a pathological feature of sporadic ad. Increased pathogenic A beta generation, even in the absence of pathogenic PSEN gene mutations, is one of proposed mechanisms for sporadic ad pathogenesis. gamma-Secretase digests substrates in the transmembrane region, generating A beta peptide intermediates of various lengths. The end products, shorter A beta 40 and A beta 38 peptides, are less neurotoxic, whereas PSEN gene mutations increase the production ratio of longer, neurotoxic A beta species such as A beta 42, an intermediate in A beta 38 production. gamma-Secretase activity or structures is altered because of its aberrant membrane localization or changes in the ambient environment such as luminal acidification. Interestingly, gamma-secretase has a pH sensor in presenilins.