Mice hemizygous for this BRI-Abeta42 transgene are viable and fertile with a normal lifespan and no obvious behavioral abnormalities. Transgenic BRI-Abeta42 mRNA is expressed in a pattern characteristic of the mouse prion protein promoter; highest transgene expression levels are detected in the cerebellar granule cells and hippocampus, followed by the cortex, pons, thalamus, and midbrain. Wildtype BRI protein is cleaved by furin or a furin-like protease near the COOH-terminus which releases a soluble 23 amino acid peptide. In the transgenic fusion protein, Abeta1-42 is fused to the C terminus of the BRI protein at the furin-like cleavage site such that cleavage results in efficient Abeta1-42 secretion into the lumen or extracellular space. Therefore, these mice specifically express the Abeta1-42 isoform in the absence of human amyloid beta protein precursor (APP) overexpression. In contrast to BRI-Abeta40 transgenic mice (Tg(Prnp-ITM2B/APP695*40)1Emcg), hemizygous BRI-Abeta42 mice accumulate detergent-insoluble amyloid-beta with age and develop cored plaques in the cerebellum at as early as three months of age. Development of forebrain pathology occurs later, and is more variable. Extracellular Abeta plaques are not present consistently in the hippocampus and entorhinal/piriform cortices until 12 months of age. BRI-Abeta42 mice also develop extensive congophillic amyloid angiopathy with age. These mutant mice may be useful in neurological studies of Alzheimer's disease, neurodegeneration, and amyloid plaque formation.

These BRI-Abeta42 transgenic mice harbor a mouse prion promoter-driven BRI-Abeta42 fusion construct (containing a human type 2 transmembrane protein (BRI or <i>ITM2B</i>) fused in-frame with a "wild-type APP695" cDNA sequence encoding amyloid-beta42 (Abeta42) at the furin-like cleavage site (the C-terminal 23 amino acid ABri peptide of BRI was replaced with the Abeta42 sequence)). As Abeta1-42 is fused to the C terminus of the BRI protein at the furin-like cleavage site, cleavage releases Abeta into the lumen or extracellular space, resulting in efficient secretion of Abeta1-42. Therefore, these BRI-Abeta42 transgenic mice specifically express the Abeta1-42 isoform in the absence of human amyloid beta protein precursor (APP) overexpression and may be useful in neurological studies of Alzheimer's disease, neurodegeneration, and amyloid plaque formation.

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