Chapter category: Neurodegenerative Disease
γ -Secretase and Presenilin
Ab Metabolism and Alzheimer's Disease
Edited by: Takaomi SaidoISBN: 1-58706-230-5
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Chapter authors:
Michael S. Wolfe
Because production and deposition of the amyloid-β peptide (Aβ) is intimately linked to the pathogenesis of Alzheimer's disease (AD), the proteases responsible for excising Aβ from the amyloid-β precursor protein (APP), β- and γ-secretases, are considered important therapeutic targets. β-secretase is a membraneanchored aspartyl protease in the pepsin family. In contrast, γ-secretase is a highly complex and unusual protease that catalyzes hydrolysis within the transmembrane domain of its substrates. A large body of evidence now supports the hypothesis that the catalytic component of γ-secretase is presenilin, a multipass membrane protein. Genetic analysis identified presenilins as major loci for mutations that cause familial, early onset AD. These mutations affect Aβ production by altering the specificity of γ-secretase, and knockout of presenilins eliminates γ-secretase activity. The identification of transitionstate analogue inhibitors of γ-secretase suggested an aspartyl protease mechanism. Consistent with all these findings, two conserved transmembrane aspartates in presenilin are critical for γ-secretase activity, and active site directed inhibitors of γ-secretase bind directly to presenilin. Moreover, presenilin copurifies with γ-secretase activity through size exclusion and affinity chromatography, and antibodies to presenilin can precipitate γ-secretase activity. Presenilins by themselves do not possess protease activity. Instead, presenilins are apparently part of a larger protease complex that includes the singlepass protein nicastrin and at least two other components.
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