title: Conditional inactivation of nicastrin restricts amyloid deposition in an Alzheimer's disease mouse model.
abstract: Production of Aβ by γ-secretase is a key event in Alzheimer's disease (AD). The γ-secretase complex consists of presenilin (PS) 1 or 2, nicastrin (ncstn), Pen-2, and Aph-1 and cleaves type I transmembrane proteins, including the amyloid precursor protein (APP). Although ncstn is widely accepted as an essential component of the complex required for γ-secretase activity, recent in vitro studies have suggested that ncstn is dispensable for APP processing and Aβ production. The focus of this study was to answer this controversy and evaluate the role of ncstn in Aβ generation and the development of the amyloid-related phenotype in the mouse brain. To eliminate ncstn expression in the mouse brain, we used a ncstn conditional knockout mouse that we mated with an established AD transgenic mouse model (5XFAD) and a neuronal Cre-expressing transgenic mouse (CamKIIα-iCre), to generate AD mice (5XFAD/CamKIIα-iCre/ncstn(f/f) mice) where ncstn was conditionally inactivated in the brain. 5XFAD/CamKIIα-iCre/ncstn(f/f) mice at 10 week of age developed a neurodegenerative phenotype with a significant reduction in Aβ production and formation of Aβ aggregates and the absence of amyloid plaques. Inactivation of nctsn resulted in substantial accumulation of APP-CTFs and altered PS1 expression. These results reveal a key role for ncstn in modulating Aβ production and amyloid plaque formation in vivo and suggest ncstn as a target in AD therapeutics.
authors.affiliation: Department of Cell Biology, Biomedical Research Foundation, Academy of Athens, Athens, 115 27, Greece.
authors.forename: Katia
authors.initials: K
authors.lastname: Sesele
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Thanopoulou
authors.forename: Evi
authors.initials: E
authors.lastname: Paouri
authors.forename: Eliona
authors.initials: E
authors.lastname: Tsefou
authors.forename: Apostolos
authors.initials: A
authors.lastname: Klinakis
authors.forename: Spiros
authors.initials: S
authors.lastname: Georgopoulos
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D053764:Presenilin-1 / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D052160:Benzothiazoles; D008562:Membrane Glycoproteins; D053764:Presenilin-1; D013844:Thiazoles; C413604:nicastrin protein; C009462:thioflavin T; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C045073:Cre recombinase; D019426:Integrases; D053829:Amyloid Precursor Protein Secretases
keywords: 5XFAD mice; Alzheimer's disease; amyloid; conditional knockout mice; nicastrin; γ-secretase