APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant

Robert Tamayev, Shuji Matsuda, Luca Giliberto, Ottavio Arancio, Luciano D'Adamio

Research output: Contribution to journalArticle

32 Scopus citations

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 AÎ 2-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 Î 2-, Î ±- and Î 3-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.

Original languageEnglish (US)
Pages (from-to)2501-2509
Number of pages9
JournalEMBO Journal
Volume30
Issue number12
DOIs
StatePublished - May 2011

Keywords

  • APP
  • BRI2/ITM2b
  • familial Alzheimer disease
  • familial Danish dementia
  • mouse model

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Tamayev, R., Matsuda, S., Giliberto, L., Arancio, O., & D'Adamio, L. (2011). APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant. EMBO Journal, 30(12), 2501-2509. https://doi.org/10.1038/emboj.2011.161