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Sci. Aging Knowl. Environ., 10 August 2005
Vol. 2005, Issue 32, p. tg5
[DOI: 10.1126/sageke.2005.32.tg5]
GENETICALLY ALTERED MICE
BRI-A 40 Transgenic Mice
http://sageke.sciencemag.org/cgi/content/full/2005/32/tg5
Mouse |
BRI-A 40 transgenic mice |
Genetic background |
B6C3F1 x B6 (fertilized oocytes were injected with the BRI- A 40 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 A 1-40. |
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-A 40 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. A 1-40 was fused to the BRI protein at the furin cleavage site. Cleavage at this site releases A 1-40 into the lumen or extracellular space, resulting in efficient secretion, but not intracellular accumulation, of human A 1-40 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 A 1-42 is pathogenic in Alzheimer's disease (AD), because it is the major component of senile plaques, is aggregable, and may be more neurotoxic than A 1-40 (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-A 40 transgenic mice express high levels of human A 1-40 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-A 40 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 . A 1-40 and A 1-42 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 A 1-42, 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., A 42 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
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Other comments |
In contrast to BRI-A 40 transgenic mice, BRI-A 42 transgenic mice, which express human A 1-42 fused to the BRI protein at the furin cleavage site under the control of MoPrp, thus producing a secreted form of human A 1-42 peptide, notably accumulate insoluble A 1-42 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-A 42 Transgenic Mice
Tg2576 Mice
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Keywords |
Alzheimer's disease
amyloid precursor protein
amyloid plaques
A
dementia
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Prepared by |
Qing Guo
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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., A
42 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]
Citation: BRI-A  40 Transgenic Mice. Sci. Aging Knowl. Environ. 2005 (32), tg5 (2005).
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