title: gamma-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease.
abstract: The gamma-secretase complex plays a role in Alzheimer's disease and cancer progression. The development of clinically useful inhibitors, however, is complicated by the role of the gamma-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different gamma-secretase complexes containing different Presenilin or Aph1 protein subunits are present in various tissues. Here we show that these complexes have heterogeneous biochemical and physiological properties. Specific inactivation of the Aph1B gamma-secretase in a mouse Alzheimer's disease model led to improvements of Alzheimer's disease-relevant phenotypic features without any Notch-related side effects. The Aph1B complex contributes to total gamma-secretase activity in the human brain, and thus specific targeting of Aph1B-containing gamma-secretase complexes may help generate less toxic therapies for Alzheimer's disease.
authors.affiliation: Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Serneels
authors.forename: Jérôme
authors.initials: J
authors.lastname: Van Biervliet
authors.forename: Katleen
authors.initials: K
authors.lastname: Craessaerts
authors.forename: Tim
authors.initials: T
authors.lastname: Dejaegere
authors.forename: Katrien
authors.initials: K
authors.lastname: Horré
authors.forename: Tine
authors.initials: T
authors.lastname: Van Houtvin
authors.forename: Hermann
authors.initials: H
authors.lastname: Esselmann
authors.forename: Sabine
authors.initials: S
authors.lastname: Paul
authors.forename: Martin K
authors.initials: MK
authors.lastname: Schäfer
authors.forename: Oksana
authors.initials: O
authors.lastname: Berezovska
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Ben
authors.initials: B
authors.lastname: Sprangers
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Yang
authors.forename: Patrick C
authors.initials: PC
authors.lastname: May
authors.forename: Eric
authors.initials: E
authors.lastname: Karran
authors.forename: Jens
authors.initials: J
authors.lastname: Wiltfang
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D018782:Maze Learning; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D053764:Presenilin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D010446:Peptide Fragments; D053764:Presenilin-1; D021122:Protein Subunits; D051881:Receptor, Notch1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C475155:APH1B protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; C498196:Aph1C protein, mouse; C498195:Aph1b protein, mouse