title: APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant.
abstract: An autosomal dominant mutation in the BRI2/ITM2B gene causes familial Danish dementia (FDD). Analysis of FDD(KI) mice, a mouse model of FDD genetically congruous to the human disease since they carry one mutant and one wild-type Bri2/Itm2b allele, has shown that the Danish mutation causes loss of Bri2 protein, synaptic plasticity and memory impairments. BRI2 is a physiological interactor of Aβ-precursor protein (APP), a gene associated with Alzheimer disease, which inhibits processing of APP. Here, we show that APP/Bri2 complexes are reduced in synaptic membranes of FDD(KI) mice. Consequently, APP metabolites derived from processing of APP by β-, α- and γ-secretases are increased in Danish dementia mice. APP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for APP metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that APP and BRI2 functionally interact, and that the neurological effects of the Danish form of BRI2 only occur when sufficient levels of APP are supplied by two alleles. This evidence establishes a pathogenic sameness between familial Danish and Alzheimer's dementias.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Tamayev
authors.forename: Shuji
authors.initials: S
authors.lastname: Matsuda
authors.forename: Luca
authors.initials: L
authors.lastname: Giliberto
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics*; D000818:Animals; D003704:Dementia / Q000235:genetics*; D003718:Denmark; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006580:Genetic Carrier Screening; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008569:Memory Disorders / Q000235:genetics* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050506:Mutant Chimeric Proteins / Q000235:genetics; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; C492300:Itm2b protein, mouse; D008565:Membrane Proteins; D050506:Mutant Chimeric Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)