Posted 30 September 2004

General Information

cDNA construction: A 1.35-kb porcine TGF-β1 cDNA was kindly provided by Dr. A. H. Greenberg (Manitoba Institute of Cell Biology, Winnipeg, Canada).

The cDNA was inserted into the first exon of a modified mouse glial fibrillary acidic protein (GFAP) gene. It is mutated to encode serines instead of cysteines at amino acid positions 223 and 225 to ensure that TGF-β1 is secreted as a bioactive peptide.

Mutation: TGF-β1

Promoter:  mouse GFAP

Origin: BALB/c × SJL background and heterozygous for TGF-β1

Background: C57BL/6J; generations 10.

Breeding: Mice breed well.

Phenotype

Neuropathological analysis

T115 Heterozygous mice express large amounts of the transgene associated with enhanced expression of endogenous TGF-β1. Cortices of tg mice demonstrate a significant up-regulation of the mRNAs encoding APP isoforms compared with wild-type mice. Overexpression of the anti-inflammatory cytokine TGF-β1 in tg mice induces higher expression of endogenous APP isoforms and increased Aβ generation in cerebral tissues. 6-month-old mice overexpressing TGF-β1 display increased endogenous APP expression and Aβ production in vitro.

Transgene copy number: approximately 10

mRNA levels: -/+ 200 +/+ 400

Hydrocephalus: Never observed

Other pathology: Cerebrovascular astrocytosis and amyloid deposition is age- and dose-related. In addition, genetic background of strain modulates pathology.

Behavioral

N/A

Availability

Licensing/academic distribution contact information:

Contact: Tony Wyss-Coray
VA Palo Alto Health Care System, Mailcode 154W, Bldg 100 D3-141
Stanford University, 300 Pasteur Drive, Stanford, CA 94305
Tel: 650-852-3220, Fax: 650-849-0434
Email: twc@stanford.edu

Patents: None

References

Primary:

Lesne S, Docagne F, Gabriel C, Liot G, Lahiri DK, Buee L, Plawinski L, Delacourte A, MacKenzie ET, Buisson A, Vivien D. Transforming growth factor-beta 1 potentiates amyloid-beta generation in astrocytes and in transgenic mice. J. Biol. Chem. 278:18408-18418, 2003. Abstract

Associated:

Wyss-Coray T, Feng L, Masliah E, Ruppe MD, Lee HS, Toggas SM, Rockenstein EM, Mucke L: Increased central nervous system production of extracellular matrix components and development of hydrocephalus in transgenic mice overexpressing transforming growth factor-ß1. Am J Pathol 147:53-67, 1995. Abstract

Wyss-Coray, T., Borrow, P., Brooker, M.J., and Mucke, L. Astroglial overproduction of TGF-b1 enhances inflammatory central nervous system disease in transgenic mice. J. Neuroimmunol. 77:45-50, 1997. Abstract

Wyss-Coray, T., Masliah, E., Mallory, M., McConlogue, L., Johnson-Wood, K., Lin, C., and Mucke, L. (1997) Amyloidogenic role of cytokine TGF-b1 in transgenic mice and Alzheimer's disease. Nature 389:603-606. Abstract