title: Increased AβPP processing in familial Danish dementia patients.
abstract: An autosomal dominant mutation in the BRI2/ITM2B gene causes Familial Danish Dementia (FDD). We have generated a mouse model of FDD, called FDDKI, genetically congruous to the human disease. These mice carry one mutant and one wild type Bri2/Itm2b allele, like FDD patients. Analysis of FDDKI mice and samples from human patients has shown that the Danish mutation causes loss of Bri2 protein. FDDKI mice show synaptic plasticity and memory impairments. BRI2 is a physiological interactor of amyloid-β protein precursor (AβPP), a gene associated with Alzheimer's disease, which inhibits processing of AβPP. AβPP/Bri2 complexes are reduced in synaptic membranes of FDDKI mice. Consequently, AβPP metabolites derived from processing of AβPP by β-, α-, and γ-secretases are increased in Danish dementia mice. AβPP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for AβPP-metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that AβPP and BRI2 functionally interact. Here, we have investigated whether AβPP processing is altered in FDD patients' brain samples. We find that the levels of several AβPP metabolites, including Aβ, are significantly increased in the brain sample derived from an FDD patient. Our data are consistent with the findings in FDDKI mice, and support the hypothesis that the neurological effects of the Danish form of BRI2 are caused by toxic AβPP metabolites, suggesting that Familial Danish and Alzheimer's dementias share common pathogenic mechanisms.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Shuji
authors.initials: S
authors.lastname: Matsuda
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; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000009:adverse effects / Q000096:biosynthesis* / Q000235:genetics; D001923:Brain Chemistry / Q000235:genetics; D002386:Cataract / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D002524:Cerebellar Ataxia / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D003638:Deafness / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D003704:Dementia / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000009:adverse effects / Q000096:biosynthesis / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C492300:Itm2b protein, mouse; D008565:Membrane Proteins