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

γ-Secretase cleaves type I transmembrane proteins in a hydrophobic membrane environment following ectodomain shedding. Mutations in PSEN genes, encoding the catalytic subunits of γ-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-β (Aβ) by intramembrane cleavage of membrane-associated amyloid-β protein precursor (APP) carboxyl-terminal fragment β, which is generated via primary cleavage of APP by β-site APP cleaving enzyme 1. The longer Aβ is prone to aggregate and accumulate in the brain; however, the accumulation of Aβ in brain is also a pathological feature of sporadic ad. Increased pathogenic Aβ generation, even in the absence of pathogenic PSEN gene mutations, is one of proposed mechanisms for sporadic ad pathogenesis. γ-Secretase digests substrates in the transmembrane region, generating Aβ peptide intermediates of various lengths. The end products, shorter Aβ40 and Aβ38 peptides, are less neurotoxic, whereas PSEN gene mutations increase the production ratio of longer, neurotoxic Aβ species such as Aβ42, an intermediate in Aβ38 production. γ-Secretase activity or structures is altered because of its aberrant membrane localization or changes in the ambient environment such as luminal acidification. Interestingly, γ-secretase has a pH sensor in presenilins.