Species: Mouse
Genes: ITM2B (BRI2)
Mutations: BRI2: Familial Danish Dementia (FDD) duplication
Modification: ITM2B (BRI2): Transgenic
Disease Relevance: Familial Danish Dementia, Alzheimer's Disease, Cerebral Amyloid Angiopathy
Strain Name: Tg(Prnp-ITM2B*)6Jckr and Tg(Prnp-ITM2B*)7Jckr
Genetic Background: C57BL/6J
Availability: Available through Mathias Jucker

This transgenic line bears a mutation that causes Familial Danish Dementia (FDD), a rare autosomal dominant disorder characterized by cerebral deposition of Danish-amyloid (ADan), neuro-inflammation, and neurofibrillary tangles (Vidal et al., 2000). The FDD mutation is a 10-nucleotide duplication just before the stop codon of the BRI2 gene, resulting in a C-terminally elongated precursor protein (Dan-amyloid precursor protein, or ADanPP). The C-terminal fragment is generated through normal proteolytic processing, but with the FDD mutation the C-terminal cleavage product (ADan) is longer than normal and prone to aggregation. The mice express higher levels of both the human full-length precursor protein and the cleaved peptide, several fold over that of the endogenous mouse forms. Two lines of transgenic mice (expressing the transgene at different levels) have been characterized at 2, 4, 10, and 18 months of age for ADan pathology and protein levels.

ADan deposition is first observed in the hippocampus and meningeal vessels at two months, and increases with age. By 18 months, ADan deposition is widespread throughout the brain. The majority of amyloid deposits are associated with the vasculature, where they integrate into the endothelial and vascular basement membrane and destroy the integrity of the vessel wall and lead to microhemorrhages. Parenchymal amyloid plaques surrounded by microglia and dystrophic neurites are also present.

Behaviorally, six month-old and 18-20 month-old mice have been studied. Mice 18-20 months of age exhibited both motor and spatial learning defects in the Morris water maze, and increased anxiety in open field. No impairments were observed in six month-old mice. Alopecia and kyphosis are also observed, and adult mice fail to gain weight with age (Coomaraswamy et al., 2010).

Phenotype Characterization

COMMENTS / QUESTIONS

1. • Andre Delacourte
     Inserm
   • Posted: 28 Apr 2010
   • Paper: Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease.

   It is now possible, using sophisticated molecular engineering, to support all types of hypotheses, both ways. The truth is in therapeutical trials.

   View all comments by Andre Delacourte

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References

Paper Citations

1. Vidal R, Revesz T, Rostagno A, Kim E, Holton JL, Bek T, Bojsen-Møller M, Braendgaard H, Plant G, Ghiso J, Frangione B. A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4920-5. PubMed.
2. Coomaraswamy J, Kilger E, Wölfing H, Schäfer C, Kaeser SA, Wegenast-Braun BM, Hefendehl JK, Wolburg H, Mazzella M, Ghiso J, Goedert M, Akiyama H, Garcia-Sierra F, Wolfer DP, Mathews PM, Jucker M. Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease. Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7969-74. PubMed.

Other Citations

1. Mathias Jucker

Further Reading

No Available Further Reading