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The Catalytic Core of γ-Secretase: Presenilin Revisited

[ Vol. 5 , Issue. 2 ]


Harald Steiner   Pages 147 - 157 ( 11 )


Mutations in the presenilin 1 (PS1) gene are the major cause of familial Alzheimers disease (AD). They effect an increased production of the highly neurotoxic 42 amino acid variant of the amyloid-β peptide (Aβ), which is believed to initiate the disease. Aβ is the product of two consecutive cleavages of the β-amyloid precursor protein (APP) by two proteases, β-secretase and γ-secretase. The latter enzyme has been identified as an intramembrane-cleaving multiprotein complex that apart from APP cleaves a large number of other type I transmembrane proteins. PS1 and its homologue PS2 are essential for γ-secretase cleavage and more than a decade after their discovery it is now firmly established that they function as catalytic subunits of γ-secretase. This review recapitulates the findings that led to this conclusion as well as the further progress made on the function of PS as γ-secretase since then.


Alzheimer's disease, Amyloid β-peptide, presenilin, γ-secretase


Adolf-Butenandt-Institute,Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Schillerstr. 44, Ludwig-Maximilians-University, 80336 Munich,Germany.

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