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- Title
Memory Deficits Due to Familial British Dementia BRI2 Mutation Are Caused by Loss of BRI2 Function Rather than Amyloidosis.
- Authors
Robert Tamayev; Giliberto, Luca; Wei Li; d'Abramo, Cristina; Arancio, Ottavio; Vidal, Ruben; D'Adamio, Luciano
- 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 dementiamaybe multifaceted and involve other mechanisms, such as loss of function due to pathogenic mutations. Mouse models of human dementia invariably use transgenic expression systems (LaFerlaandOddo,2005;McGowanet al., 2006; Vidal et al., 2009;Coomaraswamyet al., 2010) thatdonot reflect the genotypes ofhuman disease and cannot replicate loss of function. Therefore, we generated a knock-in (KI) mouse model ofFBD(FBDKI ) genetically congruous with the human disease. FBD is caused by a mis sense 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.
- Subjects
DEMENTIA; ALZHEIMER'S disease; NEURODEGENERATION; AMYLOIDOSIS; TRANSGENIC mice; MEMORY loss; GENETIC mutation
- Publication
Journal of Neuroscience, 2010, Vol 30, Issue 44, p14915
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3917-10.2010