title: The mechanism of γ-Secretase dysfunction in familial Alzheimer disease.
abstract: The mechanisms by which mutations in the presenilins (PSEN) or the amyloid precursor protein (APP) genes cause familial Alzheimer disease (FAD) are controversial. FAD mutations increase the release of amyloid β (Aβ)42 relative to Aβ40 by an unknown, possibly gain-of-toxic-function, mechanism. However, many PSEN mutations paradoxically impair γ-secretase and 'loss-of-function' mechanisms have also been postulated. Here, we use kinetic studies to demonstrate that FAD mutations affect Aβ generation via three different mechanisms, resulting in qualitative changes in the Aβ profiles, which are not limited to Aβ42. Loss of ɛ-cleavage function is not generally observed among FAD mutants. On the other hand, γ-secretase inhibitors used in the clinic appear to block the initial ɛ-cleavage step, but unexpectedly affect more selectively Notch than APP processing, while modulators act as activators of the carboxypeptidase-like (γ) activity. Overall, we provide a coherent explanation for the effect of different FAD mutations, demonstrating the importance of qualitative rather than quantitative changes in the Aβ products, and suggest fundamental improvements for current drug development efforts.
authors.affiliation: VIB Center for the Biology of Disease, Leuven, Belgium.
authors.forename: Lucía
authors.initials: L
authors.lastname: Chávez-Gutiérrez
authors.forename: Leen
authors.initials: L
authors.lastname: Bammens
authors.forename: Iryna
authors.initials: I
authors.lastname: Benilova
authors.forename: Annelies
authors.initials: A
authors.lastname: Vandersteen
authors.forename: Manasi
authors.initials: M
authors.lastname: Benurwar
authors.forename: Marianne
authors.initials: M
authors.lastname: Borgers
authors.forename: Sam
authors.initials: S
authors.lastname: Lismont
authors.forename: Lujia
authors.initials: L
authors.lastname: Zhou
authors.forename: Simon
authors.initials: S
authors.lastname: Van Cleynenbreugel
authors.forename: Hermann
authors.initials: H
authors.lastname: Esselmann
authors.forename: Jens
authors.initials: J
authors.lastname: Wiltfang
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Serneels
authors.forename: Eric
authors.initials: E
authors.lastname: Karran
authors.forename: Harrie
authors.initials: H
authors.lastname: Gijsen
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.forename: Kerensa
authors.initials: K
authors.lastname: Broersen
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology*; D000682:Amyloid / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D007700:Kinetics; D053764:Presenilin-1 / Q000378:metabolism*; D066247:Receptor, ErbB-4; D051881:Receptor, Notch1 / Q000378:metabolism
chemical_list: D000682:Amyloid; D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; C497761:NOTCH1 protein, human; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051881:Receptor, Notch1; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; D053829:Amyloid Precursor Protein Secretases