title: Memory deficits of British dementia knock-in mice are prevented by Aβ-precursor protein haploinsufficiency.
abstract: Familial British Dementia (FBD) is caused by an autosomal dominant mutation in the BRI2/ITM2B gene (Vidal et al., 1999). FBD(KI) mice are a model of FBD that is genetically congruous to the human disease, because they carry one mutant and one wild-type Bri2/Itm2b allele. Analysis of these mice has shown that the British mutation causes memory impairments due to loss of Bri2 function (Tamayev et al., 2010b). BRI2 is a physiologic inhibitor of processing of the Aβ-precursor protein (APP; Matsuda et al., 2008), a gene associated with Alzheimer's disease (Bertram et al., 2010). Here we show that APP haploinsufficiency prevents memory dysfunctions seen in FBD(KI) mice. This genetic suppression is consistent with a role for APP in the pathogenesis of memory deficits. Moreover, it provides compelling evidence that the memory dysfunctions caused by the British BRI2 mutant are dependent on endogenous APP and that BRI2 and APP functionally interact. This evidence establishes a mechanistic connection between Familial British and Alzheimer's dementias.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Tamayev
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides / Q000172:deficiency*; D000818:Animals; D003704:Dementia / Q000150:complications* / Q000235:genetics; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D008569:Memory Disorders / Q000209:etiology* / Q000517:prevention & control*; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011328:Prions / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology; D013028:Space Perception / Q000502:physiology; D014404:Tubulin / Q000378:metabolism
chemical_list: C110396:(ctm)PrP; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D011328:Prions; D014404:Tubulin