BRI-A40 Transgenic Mice

Mouse BRI-A40 transgenic mice Genetic background B6C3F1 x B6 (fertilized oocytes were injected with the BRI- A40 fusion construct). Transgenic founders were backcrossed to C3B6F1 mice and maintained on a C3B6 hybrid strain. Gene changed BRI (integral membrane protein 2B; ITM2B) and the fragment of the APP gene encoding human A1-40. Type of change Mice were engineered to produce human amyloid -peptide (A) 1-40 fused to the BRI protein under the control of the mouse prion promoter (MoPrp). The BRI-A40 fusion construct was designed to take advantage of a property of the BRI protein. Normally, the wild-type protein is cleaved by furin or a furin-like protease near the C terminus to release a soluble 23 amino acid peptide. A1-40 was fused to the BRI protein at the furin cleavage site. Cleavage at this site releases A1-40 into the lumen or extracellular space, resulting in efficient secretion, but not intracellular accumulation, of human A1-40 peptide. Nature of protein A is produced when amyloid precursor protein (APP) is cleaved by - and -secretases at the N and C terminus of the A peptide, respectively. The intramembrane -secretase cleavage of APP generates two major forms of A, which are 40 and 42 amino acids in length. It is believed that A1-42 is pathogenic in Alzheimer's disease (AD), because it is the major component of senile plaques, is aggregable, and may be more neurotoxic than A1-40 (see "Detangling Alzheimer's Disease"). BRI is a type 2 transmembrane protein that normally is cleaved by furin or a furin-like protease near the C terminus to release a soluble 23 amino acid peptide into the extracellular space. An abnormal form of the BRI precursor protein is responsible for the deposition of a unique amyloid-forming protein, ABri, in familial British dementia (FBD). In FBD, BRI is elongated by 11 amino acids because of a point mutation that prevents recognition of the normal stop codon, resulting in the secretion of an insoluble 34 amino acid peptide. Phenotype BRI-A40 transgenic mice express high levels of human A1-40 peptide but do not develop overt amyloid pathology in the brain by 24 months of age. The mice display neither neuronal loss nor prominent neurofibrillary pathology. BRI-A40 mice have a normal life span and do not display obvious behavioral abnormalities. Corresponding human phenotype Amyloid plaques, one of the characteristic lesions found in the brains of patients with AD, primarily consist of extracellular deposits of A. A1-40 and A1-42 are generated by cleavage of APP by - and -secretases. The -secretase was recently identified as a novel membrane-bound aspartyl protease (named BACE1, Asp2, or memapsin 2), and -secretase is a protein complex consisting of presenilin, nicastrin, Aph-1, Pen-2, and possibly other protein subunits (see Wolfe Perspective). It is generally believed that aberrant processing of APP leading to increased production and aggregation of A1-42, which can be caused by mutations in APP and presenilins, may play a central role in the pathogenesis of AD. Primary reference E. McGowan, F. Pickford, J. Kim, L. Onstead, J. Eriksen, C. Yu, L. Skipper, M. P. Murphy, J. Beard, P. Das et al., A42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47, 191-199 (2005). Additional references See below. Source These mice are not commercially available. Please contact: Eileen McGowan or Todd Golde Department of Neuroscience Mayo Clinic College of Medicine Jacksonville, FL 32224 E-mail: mcgowan.eileen{at}mayo.edu or golde.todd{at}mayo.edu Other comments In contrast to BRI-A40 transgenic mice, BRI-A42 transgenic mice, which express human A1-42 fused to the BRI protein at the furin cleavage site under the control of MoPrp, thus producing a secreted form of human A1-42 peptide, notably accumulate insoluble A1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy, and diffuse A deposits in the brain. Other links Online Mendelian Inheritance in Man: BRI APP SAGE KE's Genes/Interventions database: APP SAGE KE's Genetically Altered Mice: BRI-A42 Transgenic Mice Tg2576 Mice Keywords Alzheimer's disease amyloid precursor protein amyloid plaques A dementia Prepared by Qing Guo

1. P. A. Lewis, S. Piper, M. Baker, L. Onstead, M. P. Murphy, J. Hardy, R. Wang, E. McGowan, T. E. Golde, Expression of BRI-amyloid peptide fusion proteins: A novel method for specific high-level expression of amyloid peptides. Biochim. Biophys. Acta 1537, 58-62 (2001).[Medline]
2. S. H. Kim, R. Wang, D. J. Gordon, J. Bass, D. F. Steiner, G. Thinakaran, D. G. Lynn, S. C. Meredith, S. S. Sisodia, Familial British dementia: Expression and metabolism of BRI. Ann. N. Y. Acad. Sci. 920, 93-99 (2000).[Medline]
3. E. McGowan, F. Pickford, J. Kim, L. Onstead, J. Eriksen, C. Yu, L. Skipper, M. P. Murphy, J. Beard, P. Das et al., A42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47, 191-199 (2005).[CrossRef][Medline]
4. C. Schwab, M. Hosokawa, H. Akiyama, P. L. McGeer, Familial British dementia: Colocalization of furin and ABri amyloid. Acta Neuropathol. (Berl.) 106, 278-284 (2003).[CrossRef][Medline]