Memory deficits due to familial British dementia BRI2 mutation are caused by loss of BRI2 function rather than amyloidosis

Robert Tamayev, Luca Giliberto, Wei Li, Cristina D'Abramo, Ottavio Arancio, Ruben Vidal, Luciano D'Adamio

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Familial dementias, which include Alzheimer disease (AD), familial British dementia (FBD), and familial Danish dementia (FDD), are caused by dominantly inherited autosomal mutations and are characterized by the production of amyloidogenic peptides, neurofibrillary tangles (NFTs) and neurodegeneration (St George-Hyslop and Petit, 2005; Garringer et al., 2009). The prevailing pathogenic theory, the "amyloid cascade hypothesis" (Hardy and Selkoe, 2002), posits that the accumulation of amyloidogenic peptides triggers tauopathy, neurodegeneration, and cognitive and behavioral changes. However, this hypothesis is yet to be validated, and causes of dementia may be multifaceted and involve other mechanisms, such as loss of function due to pathogenic mutations. Mouse models of human dementia invariably use transgenic expression systems (LaFerla and Oddo, 2005; McGowanet al., 2006; Vidal et al., 2009; Coomaraswamy et al., 2010) that do not reflect the genotypes of human disease and cannot replicate loss of function. Therefore, we generated a knock-in (KI) mouse model of FBD (FBDKI) genetically congruous with the human disease. FBD is caused by amissense mutation at the stop codon of the BRI2 gene (Vidaletal., 1999) and, like FBD patients, FBDKI mice carry this mutation in one of the two murine Bri2 alleles. We report that the British mutation drastically reduces expression of mature BRI2 in both KI mice and human FBD brains. This deficit is associated with severe hippocampal memory deficits in FBDKI mice. Remarkably, these animals showed no cerebral amyloidosis and tauopathy. Bri2+/-mice present memory deficits similar to those in FBDKI animals. Collectively, these results indicate that the British BRI2 mutation underlies abnormal memory due to loss of BRI2 function and independently of histopathological alterations typically evident in advanced neurodegenerative disease.

Original languageEnglish (US)
Pages (from-to)14915-14924
Number of pages10
JournalJournal of Neuroscience
Volume30
Issue number44
DOIs
StatePublished - Nov 3 2010

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Memory Disorders
Amyloidosis
Mutation
Tauopathies
Dementia
Peptides
Neurofibrillary Tangles
Terminator Codon
Amyloid
Neurodegenerative Diseases
Familial British Dementia
Alzheimer Disease
Alleles
Genotype
Brain
Genes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Memory deficits due to familial British dementia BRI2 mutation are caused by loss of BRI2 function rather than amyloidosis. / Tamayev, Robert; Giliberto, Luca; Li, Wei; D'Abramo, Cristina; Arancio, Ottavio; Vidal, Ruben; D'Adamio, Luciano.

In: Journal of Neuroscience, Vol. 30, No. 44, 03.11.2010, p. 14915-14924.

Research output: Contribution to journalArticle

Tamayev, Robert ; Giliberto, Luca ; Li, Wei ; D'Abramo, Cristina ; Arancio, Ottavio ; Vidal, Ruben ; D'Adamio, Luciano. / Memory deficits due to familial British dementia BRI2 mutation are caused by loss of BRI2 function rather than amyloidosis. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 44. pp. 14915-14924.
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AU - Arancio, Ottavio

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