title: Interaction of ApoE3 and ApoE4 isoforms with an ITM2b/BRI2 mutation linked to the Alzheimer disease-like Danish dementia: Effects on learning and memory.
abstract: Mutations in Amyloid β Precursor Protein (APP) and in genes that regulate APP processing--such as PSEN1/2 and ITM2b/BRI2--cause familial dementia, such Familial Alzheimer disease (FAD), Familial Danish (FDD) and British (FBD) dementias. The ApoE gene is the major genetic risk factor for sporadic AD. Three major variants of ApoE exist in humans (ApoE2, ApoE3, and ApoE4), with the ApoE4 allele being strongly associated with AD. ITM2b/BRI2 is also a candidate regulatory node genes predicted to mediate the common patterns of gene expression shared by healthy ApoE4 carriers and late-onset AD patients not carrying ApoE4. This evidence provides a direct link between ITM2b/BRI2 and ApoE4. To test whether ApoE4 and pathogenic ITM2b/BRI2 interact to modulate learning and memory, we crossed a mouse carrying the ITM2b/BRI2 mutations that causes FDD knocked-in the endogenous mouse Itm2b/Bri2 gene (FDDKI mice) with human ApoE3 and ApoE4 targeted replacement mice. The resultant ApoE3, FDDKI/ApoE3, ApoE4, FDDKI/ApoE4 male mice were assessed longitudinally for learning and memory at 4, 6, 12, and 16-17 months of age. The results showed that ApoE4-carrying mice displayed spatial working/short-term memory deficits relative to ApoE3-carrying mice starting in early middle age, while long-term spatial memory of ApoE4 mice was not adversely affected even at 16-17 months, and that the FDD mutation impaired working/short-term spatial memory in ApoE3-carrying mice and produced impaired long-term spatial memory in ApoE4-carrying mice in middle age. The present results suggest that the FDD mutation may differentially affect learning and memory in ApoE4 carriers and non-carriers.
authors.affiliation: Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, United States.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Biundo
authors.affiliation: Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, United States.
authors.forename: Keita
authors.initials: K
authors.lastname: Ishiwari
authors.affiliation: Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, United States.
authors.forename: Dolores
authors.initials: D
authors.lastname: Del Prete
authors.affiliation: Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, United States. Electronic address: luciano.dadamio@einstein.yu.edu.
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D002386:Cataract / Q000235:genetics* / Q000523:psychology; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000523:psychology; D003638:Deafness / Q000235:genetics* / Q000523:psychology; D003704:Dementia / Q000235:genetics* / Q000523:psychology; D006801:Humans; D007858:Learning / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D020033:Protein Isoforms; D065852:Spatial Memory / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; C492300:Itm2b protein, mouse; D008565:Membrane Proteins; D020033:Protein Isoforms
keywords: Alzheimer disease; ApoE; BRI2; Familial Danish dementia