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TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice

Nature Medicine volume 7, pages 612–618 (2001)Cite this article

Abstract

Abnormal accumulation of the amyloid-β peptide (Aβ) in the brain appears crucial to pathogenesis in all forms of Alzheimer disease (AD), but the underlying mechanisms in the sporadic forms of AD remain unknown. Transforming growth factor β1 (TGF-β1), a key regulator of the brain's responses to injury and inflammation, has been implicated in Aβ deposition in vivo. Here we demonstrate that a modest increase in astroglial TGF-β1 production in aged transgenic mice expressing the human β-amyloid precursor protein (hAPP) results in a three-fold reduction in the number of parenchymal amyloid plaques, a 50% reduction in the overall Aβ load in the hippocampus and neocortex, and a decrease in the number of dystrophic neurites. In mice expressing hAPP and TGF-β1, Aβ accumulated substantially in cerebral blood vessels, but not in parenchymal plaques. In human cases of AD, Aβ immunoreactivity associated with parenchymal plaques was inversely correlated with Aβ in blood vessels and cortical TGF-β1 mRNA levels. The reduction of parenchymal plaques in hAPP/TGF-β1 mice was associated with a strong activation of microglia and an increase in inflammatory mediators. Recombinant TGF-β1 stimulated Aβ clearance in microglial cell cultures. These results demonstrate that TGF-β1 is an important modifier of amyloid deposition in vivo and indicate that TGF-β1 might promote microglial processes that inhibit the accumulation of Aβ in the brain parenchyma.

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Figure 1: TGF-β1 reduces amyloid plaque burden and inhibits Aβ accumulation in brain parenchyma.
Figure 2: Change in distribution and overall decrease in hippocampal Aβ deposits in hAPP/TGF-β1 mice.
Figure 3: Localization of Aβ deposits along blood vessels in hAPP/TGF-β1 mice.
Figure 4: Inverse correlation between Aβ deposits in blood vessels and plaques and association with TGF-β1 expression levels in brains from mice and AD cases.
Figure 5: TGF-β1 increases microglia activation in aged hAPP/TGF-β1 mice and promotes Aβ clearance in cell culture.

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Acknowledgements

We thank G. Howard and S. Ordway for editorial assistance; N. Nemenzo for secretarial help; and J.C.W. Carroll, C. Goodfellow and S. Gonzales for graphics and photography. This work was supported by National Institutes of Health Grants AG-15871 (T.W.-C.), AG-5131 and AG-10689 (E.M.), AG-11385 (L.M.), and by the Alzheimer's Association (T.W.-C.).

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Authors and Affiliations

  1. Gladstone Institute of Neurological Disease, University of California, San Francisco, California, USA

    Tony Wyss-Coray, Carol Lin, Fengrong Yan, Gui-Qiu Yu, Michelle Rohde & Lennart Mucke

  2. Department of Neurology, University of California, San Francisco, California, USA

    Tony Wyss-Coray & Lennart Mucke

  3. Neuroscience Program, University of California, San Francisco, California, USA

    Lennart Mucke

  4. Elan Pharmaceuticals, South San Francisco, California, USA

    Lisa McConlogue

  5. Departments of Neurosciences and Pathology, University of California, San Diego, La Jolla, California, USA

    Eliezer Masliah

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

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Wyss-Coray, T., Lin, C., Yan, F. et al. TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice. Nat Med 7, 612–618 (2001). https://doi.org/10.1038/87945

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