Sci. Aging Knowl. Environ., 10 August 2005
Vol. 2005, Issue 32, p. tg6
GENETICALLY ALTERED MICE
BRI-A42 Transgenic Mice
||BRI-A42 transgenic mice
||B6C3F1 x B6 (fertilized oocytes were injected with the BRI-A42 fusion construct). Transgenic founders were backcrossed to C3B6F1 mice and maintained on a C3B6 hybrid strain.
||BRI (integral membrane protein 2B; ITM2B) and the fragment of the APP gene encoding human A1-42.
|Type of change
||Mice were engineered to produce human amyloid -peptide (A) 1-42 fused to the BRI protein under the control of the mouse prion promoter (MoPrp). The BRI-A42 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. A1-42 was fused to the BRI protein at the furin cleavage site. Cleavage at this site releases A1-42 into the lumen or extracellular space, resulting in efficient secretion, but not intracellular accumulation, of human A1-42 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.
||BRI-A42 transgenic mice express high levels of human A1-42 peptide, accumulate detergent-insoluble A, and develop compact amyloid plaques [similar to the pathology displayed by Tg2576 mice (which produce a mutant form of human APP and represent a model of AD) except for the presence of a large number of plaques in the cerebellum in BRI-A42 mice], reactive gliosis, congophilic amyloid angiopathy (which mimics the pattern of amyloid deposition seen in FBD), and diffuse A deposits in the brain. The pathology was seen as early as 3 months of age and was enhanced when BRI-A42 mice were crossed with Tg2576 mice. However, the mice had neither neuronal loss nor prominent neurofibrillary pathology. BRI-A42 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.
||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).
||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: email@example.com or firstname.lastname@example.org
||In contrast to BRI-A42 transgenic mice, BRI-A40 transgenic mice, which express high levels of human A1-40 fused to the BRI protein at the furin cleavage site under the control of MoPrp, do not develop overt amyloid pathology in the brain by 24 months of age.
||Online Mendelian Inheritance in Man:
SAGE KE's Genes/Interventions database:
SAGE KE's Genetically Altered Mice:
BRI-A40 Transgenic Mice
amyloid precursor protein
August 10, 2005
- 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]
- 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]
- 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]
- 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]
42 Transgenic Mice. Sci. Aging Knowl. Environ. 2005
(32), tg6 (2005).