Mutations: BRI2: Familial Danish Dementia (FDD) duplication
Modification: BRI2: Transgenic
Disease Relevance: Familial Danish Dementia, Alzheimer's Disease, Cerebral Amyloid Angiopathy
Strain Name: N/A
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).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Synaptic Loss
- Changes in LTP/LTD
Vascular amyloid deposits and punctate parenchymal aggregates first occur in the hippocampus and increase with age, spreading throughout the brain, including the cortex, amygdala, thalamus, and brainstem in hemizygous mice.
Astrogliosis and microgliosis increase with age and increasing ADan-amyloid deposition.
Changes in LTP/LTD
The only ages tested were 6 months and 18-20 months. Mice 18-20 months of age exhibited both motor and spatial learning defects in the Morris water maze, and increased anxiety in the open field test. No impairments were observed in 6 month-old mice.
- 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.
- 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.
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