Species: Mouse
Genes: ITM2B (BRI2)
Mutations: BRI2: Familial Danish Dementia (FDD) duplication
Modification: ITM2B (BRI2): Transgenic
Disease Relevance: Familial Danish Dementia, Cerebral Amyloid Angiopathy, Alzheimer's Disease
Strain Name: N/A
Genetic Background: Hybrid C3HeB/FeJ embryo; crossed to C57BL/6J
Availability: Available through Ruben Vidal

Summary

This transgenic mouse is a model for Familial Danish Dementia (FDD), a rare autosomal dominant neurodegenerative disease caused by an insertion mutation in the BRI(2) gene. BRI(2), also known as ITM2B, is located on the long arm of chromosome 13 and encodes a transmembrane protein of unknown biological function. The insertion of 10 nucleotides causes a frame-shift in the BRI(2) sequence, and generates the Danish amyloid precursor protein (ADanPP), which is cleaved to form an amyloidogenic peptide known as the Danish amyloid subunit (ADan). Like Aβ, ADan deposits in the brain parenchyma and cerebral vessels, but it is more abundant in the vasculature and leads to a prominent CAA phenotype. Clinically, FDD is characterized by a gradual loss of vision, impaired hearing, ataxia, slurred speech, gait disturbances, psychosis, and dementia.

Like patients affected by FDD, these mice develop significant vascular amyloid deposition as well as parenchymal deposits of ADan. Amyloid deposition is age-dependent: between one and six months of age, no obvious pathology is observed; around seven months the mice begin to develop amyloid in cerebellar vessels accompanied by loss of smooth muscle cells. Numerous GFAP-positive reactive astrocytes and microglia are associated with the amyloid deposits. The mice also develop intracellular and extracellular deposition of oligomeric forms of ADan as well as tau immunoreactive deposits in neuropil, but no neurofibrillary tangles. Behaviorally, the mice develop abnormal grooming behavior with age, but a full behavioral/cognitive characterization has not been reported (Vidal et al., 2008).

Tg-FDD mice may also be relevant to the study of cerebral amyloidosis and AD.

Modification Details

The transgene, driven by the mouse prion promoter (Prnp), consists of the 795 form of human BRI(2) with a 10-nucleotide duplication-insertion (TTTAATTTGT).

Related models

A double transgenic animal has been generated by crossing Tg-FDD mice with a line of mutant Tau mice that express 4-repeat tau with the P301S mutation. The resulting double transgenics, known as Tg-FDD-Tau, have significantly greater tau deposition than the Tg-Tau mice alone, as well as other changes in tau metabolism and decrease in synaptophysin (Garringer et al., 2013).

COMMENTS / QUESTIONS

1. • Nikolaos K. Robakis
     Mount Sinai School of Medicine, NYU
   • Posted: 29 May 2008
   • Paper: Cerebral amyloid angiopathy and parenchymal amyloid deposition in transgenic mice expressing the Danish mutant form of human BRI2.

   This paper shows the generation of a novel model of cerebral (non-Aβ) amyloid deposition. The authors generated transgenic mice expressing a mutant form of the BRI gene, found in patients affected by familial Danish dementia (FDD). FDD is a rare inherited disease that causes progressive dementia that, like AD, is neuropathologically characterized by amyloid deposition (ADan), neurofibrillary tangle formation (identical to that seen in AD), and neuronal cell loss. This model provides an exciting new tool in which to study the abnormal changes in the brain that lead to dementia. Comparing the similarities and differences of these two related neurological diseases may provide important clues to how AD develops.

   View all comments by Nikolaos K. Robakis

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References

Paper Citations

1. Vidal R, Barbeito AG, Miravalle L, Ghetti B. Cerebral amyloid angiopathy and parenchymal amyloid deposition in transgenic mice expressing the Danish mutant form of human BRI2. Brain Pathol. 2009 Jan;19(1):58-68. PubMed.
2. Garringer HJ, Murrell J, Sammeta N, Gnezda A, Ghetti B, Vidal R. Increased tau phosphorylation and tau truncation, and decreased synaptophysin levels in mutant BRI2/tau transgenic mice. PLoS One. 2013;8(2):e56426. PubMed.

Other Citations

1. Ruben Vidal

Further Reading