Research Models

BRI-Aβ42 (BRI2-Aβ42)

Synonyms: BRI-Abeta42

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Species: Mouse
Modification: Transgenic
Disease Relevance: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Strain Name: B6.Cg-Tg(Prnp-ITM2B/APP695*42)A12Emcg/J
Genetic Background: B6C3, backcrossed to C57BL/6J to generate congenic strain
Availability: The Jackson Lab: Stock# 007182; Cryopreserved

Summary

These transgenic mice overexpress Aβ42 without overexpressing APP. They contain a fusion construct of the BRI protein, which is involved in amyloid deposition in Familial British Dementia (FBD) and Familial Danish Dementia (FDD), and Aβ42. Twenty-three amino acids at the C-terminal of the BRI protein were replaced with the human Aβ42 sequence in order to generate secreted Aβ42 by taking advantage of a naturally ocurring furin-like cleavage site in the BRI protein.

Hemizygous mice are viable and fertile with a normal lifespan and no obvious behavioral abnormalities. Transgene expression corresponds with the characteristic expression pattern of the mouse prion protein promoter with highest expression in cerebellar granule cells and hippocampus, followed by the cortex, pons, thalamus, and midbrain (McGowen et al., 2005).

Congenic mice were generated from an original founder line (line 12e) that exhibited high plasma levels of Aβ42. They were first maintained on a mixed B6C3 background (The Jackson Lab: Stock# 007002) and then backcrossed to C57BL/6J for at least five generations to generate a congenic strain.

As described on the mixed background, hemizygous BRI-Aβ42 mice accumulate detergent-insoluble amyloid-β with age and develop cored plaques as early as three months in the molecular layer of the cerebellum in contrast to BRI-Aβ40 mice on a mixed background which do not develop overt amyloid pathology. Forebrain pathology occurs later than cerebellar pathology and is more variable. Extracellular Aβ plaques are not consistently present in the hippocampus and entorhinal/piriform cortices until twelve months. BRI-Aβ42 mice also develop extensive congophillic amyloid angiopathy with age (McGowen et al., 2005). Despite accumulating amyloid, hemizygous mice on a mixed background (C57/B6//C3H) have intact cognition as measured by fear conditioning at twelve and 14-17 months (Kim et al., 2013).

Modification Details

Construct encodes a fusion protein of the BRI protein and Aβ42 driven by the mouse prion promoter. Aβ42 is secreted through proteolytic cleavage of the protein at a furin cleavage site immediately preceding Aβ42.

Phenotype Timeline

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Observed

Absent

  • Tangles
  • Neuronal Loss
  • Cognitive Impairment

Unknown

Plaques

Detergent-insoluble amyloid-β and cored plaques as early as three months in the cerebellum. Variable forebrain pathology later with extracellular Aβ plaques in the hippocampus and entorhinal/piriform cortices by 12 months. Extensive congophillic amyloid angiopathy.

Tangles

Absent.

Neuronal Loss

Absent.

Gliosis

Plaque-associated reactive gliosis as measured by GFAP immunostaining.

Cognitive Impairment

On a mixed (C57/B6//C3H) background hemizygous mice have intact cognition as measured by fear conditioning at 12 months and 14-17 months despite accumulating amyloid.

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References

Paper Citations

  1. . Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron. 2005 Jul 21;47(2):191-9. PubMed.
  2. . Normal cognition in transgenic BRI2-Aβ mice. Mol Neurodegener. 2013 May 12;8:15. PubMed.

External Citations

  1. The Jackson Lab: Stock# 007002
  2. The Jackson Lab: Stock# 007182

Further Reading