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Amyloidogenic role of cytokine TGF-β1 in transgenic mice and in Alzheimer's disease

Nature volume 389, pages 603–606 (1997)Cite this article

Abstract

Deposition of amyloid-β peptide in the central nervous system is a hallmark of Alzheimer's disease and a possible cause of neurodegeneration1,2,3. The factors that initiate or promote deposition of amyloid-β peptide are not known. The transforming growth factor TGF-β1 plays a central role in the response of the brain to injury4,5, and increased TGF-β1 has been found in the central nervous system of patients with Alzheimer's disease6,7,8. Here we report that TGF-β1 induces amyloid-β deposition in cerebral blood vessels and meninges of aged transgenic mice overexpressing this cytokine from astrocytes. Co-expression of TGF-β1 in transgenic mice overexpressing amyloid-precursor protein, which develop Alzheimer's like pathology9,10,11, accelerated the deposition of amyloid-β peptide. More TGF-β1 messenger RNA was present in post-mortem brain tissue of Alzheimer's patients than in controls, the levels correlating strongly with amyloid-β deposition in the damaged cerebral blood vessels of patients with cerebral amyloid angiopathy. These results indicate that overexpression of TGF-β1 may initiate or promote amyloidogenesis in Alzheimer's disease and in experimental models and so may be a risk factor for developing Alzheimer's disease.

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Figure 1: TGF-β1 expression by perivascular astrocytes in TGF-β1 mice.
Figure 2: Thioflavin S-positive deposits in aged TGF-β1 mice and humans with Alzheimer's disease (AD).
Figure 3: Accelerated development of cerebrovascular amyloid deposition in hAPP/TGF-β1 bigenic mice.
Figure 4: Vascular TGF-β1 immunoreactivity in AD brains is associated with CAA.
Figure 5: TGF-β1 mRNA levels in frontal cortex of AD brains correlate with the degree of CAA.

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Acknowledgements

We thank F. Compagno and I. Samuels for technical assistance, D. Games for advice on the detection of amyloid deposits in transgenic mice, D. Schenk for amyloid-β antibodies, J. Rogers for post-mortem human brain tissue, and S. Ordway and G. Howard for editorial assistance. This work was supported by grants from the NIH and the Alzheimer's Association. T.W.-C. was partially supported by a fellowship from the Swiss National Science Foundation.

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Author notes

  1. Tony Wyss-Coray, Eliezer Masliah and Lennart Mucke: These authors contributed equally to this work.

Authors and Affiliations

  1. Gladstone Molecular Neurobiology Program and Department of Neurology, University of California, San Francisco, 94141-9100, California, USA

    Tony Wyss-Coray, Carol Lin & Lennart Mucke

  2. Neuroscience Program, University of California, San Francisco, 94143-0444, California, USA

    Lennart Mucke

  3. Departments of Neurosciences and Pathology, University of California, San Diego, La Jolla, 92093-0624, California, USA

    Eliezer Masliah & Margaret Mallory

  4. Athena Neurosciences Inc., 800 Gateway Boulevard, South San Francisco, 94080, California, USA

    Lisa McConlogue & Kelly Johnson-Wood

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  1. Tony Wyss-Coray
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Correspondence to Tony Wyss-Coray.

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Wyss-Coray, T., Masliah, E., Mallory, M. et al. Amyloidogenic role of cytokine TGF-β1 in transgenic mice and in Alzheimer's disease. Nature 389, 603–606 (1997). https://doi.org/10.1038/39321

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