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S1‐02‐04: Mouse models of British and Danish dementia
Author(s) -
Vidal Ruben
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.191
Subject(s) - mutant , genetically modified mouse , biology , neurodegeneration , transgene , amyloid (mycology) , mutation , microbiology and biotechnology , pathology , genetics , gene , medicine , disease , botany
Background: Familial British dementia (FBD) and familial Danish dementia (FDD) are two autosomal dominant neurodegenerative diseases caused by mutations in the BRI2 gene. FBD and FDD are characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal amyloid deposition, and neurofibrillary tangles. These basic neuropathological features are also shared by Alzheimer disease (AD) and some forms of prion disease. Although different amyloid peptides are deposited in these conditions, the tau deposits are antigenically, ultrastructurally and biochemically indistinguishable. This finding of similar pathological lesions supports the notion of a unifying pathologic mechanism in which accumulation of amyloidogenic peptides could trigger a complex pathological cascade leading to neurodegeneration. Methods: Expression of cDNAs encoding the human wildtype BRI2 and FBD and FDD mutant forms of BRI2 in mice was carried out using the pan-neuronal heterologous mouse prion promoter, the Syrian hamster prion promoter, the mouse Thy-1.2 promoter, and the calcium-calmodulin-dependent kinase II promoter. Knock-out of Bri2 and knock-in models of FBD and FDD were generated by classical approaches. Results: Available experimental models of amyloid deposition include transgenic mice over-expressing human mutant BRI2 carrying the Danish mutation as single BRI2 transgenic or double Danish-BRI2/mutant Tau transgenic mice. Single Danish-BRI2 transgenic mice show severe CAA, parenchymal amyloid deposition, and amyloid-associated gliosis. Expression of a mutant tau together with the Danish mutant form of human BRI2 resulted in a more complete FDD-like pathology in mice, which could not be achieved by over-expression of the Danish mutant form of human BRI2 alone. Bri2-knock out mice do not have any particular phenotype. Knock-in models of FBD and FDD did not reproduce the neuropathological features of the disease; however, they may represent important systems in which to study the molecular basis of these diseases without over-expression of the mutant BRI2 protein. Conclusions: The availability of animal models for FBD and FDD will allow the study of the molecular mechanism(s) underlying the neuronal dysfunction in these diseases and the development of potential therapeutic approaches.