Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Selkoe, D.J. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399, A23–A31 (1999).

    Article  CAS  Google Scholar 

  2. Terry, R.D., Katzman, R., Bick, K.L. & Sisodia, S.S. Alzheimer Disease. 2nd edn. (Lippincott Williams & Wilkins, Philadelphia, 1999).

    Google Scholar 

  3. Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527 (1995).

    Article  CAS  Google Scholar 

  4. Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).

    Article  CAS  Google Scholar 

  5. Sturchler-Pierrat, C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl. Acad. Sci. USA 94, 13287–13292 (1997).

    Article  CAS  Google Scholar 

  6. Nicoll, J.A.R., Roberts, G.W. & Graham, D.I. Apolipoprotein E ɛ4 allele is associated with deposition of amyloid β-protein following head injury. Nature Med. 1, 135–137 (1995).

    Article  CAS  Google Scholar 

  7. Guo, Z. et al. Head injury and the risk of AD in the MIRAGE study. Neurology 54, 1316–1323 (2000).

    Article  CAS  Google Scholar 

  8. Zlokovic, B.V. Cerebrovascular transport of Alzheimer's amyloid β and apolipoproteins J and E: Possible anti-amyloidogenic role of the blood-brain barrier. Life Sci. 59, 1483–1497 (1996).

    Article  CAS  Google Scholar 

  9. Bales, K.R. et al. Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition. Nat. Genet. 17, 263–264 (1997).

    Article  CAS  Google Scholar 

  10. Holtzman, D.M. et al. Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease. J. Clin. Invest. 103, R15–R21 (1999).

    Article  CAS  Google Scholar 

  11. Frautschy, S.A., Cole, G.M. & Baird, A. Phagocytosis and deposition of vascular β-amyloid in rat brains injected with Alzheimer β-amyloid. Am. J. Pathol. 140, 1389–1399 (1992).

    CAS  PubMed  Google Scholar 

  12. Qiu, W.Q. et al. Insulin-degrading enzyme regulates extracellular levels of amyloid β-protein by degradation. J. Biol. Chem. 273, 32730–32738 (1998).

    Article  CAS  Google Scholar 

  13. Yan, S.D., Roher, A., Schmidt, A.M. & Stern, D.M. Cellular cofactors for amyloid β-peptide-induced cell stress. Moving from cell culture to in vivo. Am. J. Pathol. 155, 1403–1411 (1999).

    Article  CAS  Google Scholar 

  14. Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999).

    Article  CAS  Google Scholar 

  15. Bard, F. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med. 6, 916–919 (2000).

    Article  CAS  Google Scholar 

  16. Giulian, D. Microglia and the immune pathology of Alzheimer disease. Am. J. Hum. Genet. 65, 13–18 (1999).

    Article  CAS  Google Scholar 

  17. Frackowiak, J. et al. Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce β-amyloid fibrils. Acta Neuropathol. 84, 225–233 (1992).

    Article  CAS  Google Scholar 

  18. Finch, C.E., Laping, N.J., Morgan, T.E., Nichols, N.R. & Pasinetti, G.M. TGF-β1 is an organizer of responses to neurodegeneration. J. Cell. Biochem. 53, 314–322 (1993).

    Article  CAS  Google Scholar 

  19. Wyss-Coray, T. et al. Amyloidogenic role of cytokine TGF-β1 in transgenic mice and Alzheimer's disease. Nature 389, 603–606 (1997).

    Article  CAS  Google Scholar 

  20. Frautschy, S.A., Yang, F., Calderón, L. & Cole, G. M. Rodent models of Alzheimer's disease: Rat Aβ infusion approaches to amyloid deposits. Neurobiol. Aging 17, 311–321 (1996).

    Article  CAS  Google Scholar 

  21. Flanders, K.C., Ren, R.F. & Lippa, C.F. Transforming growth factor-βs in neurodegenerative disease. Prog. Neurobiol. 54, 71–85 (1998).

    Article  CAS  Google Scholar 

  22. Akiyama, H. et al. Inflammation and Alzheimer's disease. Neuroinflammation Working Group. Neurobiol. Aging 21, 383–421 (2000).

    Article  CAS  Google Scholar 

  23. Roberts, A.B. & Sporn, M.B. Transforming growth factor-β, in The Molecular and Cellular Biology of Wound Repair 2nd edn. (ed. Clark, R.A.F.), 275–308 (Plenum, New York, 1996).

    Google Scholar 

  24. Wyss-Coray, T. et al. Increased central nervous system production of extracellular matrix components and development of hydrocephalus in transgenic mice overexpressing transforming growth factor-β1. Am. J. Pathol. 147, 53–67 (1995).

    CAS  PubMed  Google Scholar 

  25. Wyss-Coray, T., Lin, C., Sanan, D., Mucke, L. & Masliah, E. Chronic overproduction of TGF-β1 in astrocytes promotes Alzheimer's disease-like microvascular degeneration in transgenic mice. Am. J. Pathol. 156, 139–150 (2000).

    Article  CAS  Google Scholar 

  26. Wahl, S.M. Transforming growth factor beta (TGF-β) in inflammation: A cause and a cure. J. Clin. Immunol. 12, 61–74 (1992).

    Article  CAS  Google Scholar 

  27. Yao, J., Harvath, L., Gilbert, D. & Colton, C. Chemotaxis by a CNS macrophage, the microglia. J. Neurosci. Res. 27, 36–42 (1990).

    Article  CAS  Google Scholar 

  28. Wyss-Coray, T., Borrow, P., Brooker, M.J. & Mucke, L. Astroglial overproduction of TGF-β1 enhances inflammatory central nervous system disease in transgenic mice. J. Neuroimmunol. 77, 45–50 (1997).

    Article  CAS  Google Scholar 

  29. Hsia, A. et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc. Natl. Acad. Sci. USA 96, 3228–3233 (1999).

    Article  CAS  Google Scholar 

  30. Mucke, L. et al. High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: Synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058 (2000).

    Article  CAS  Google Scholar 

  31. Barelli, H. et al. Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid β peptides: Their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer's disease and cerebral amyloid angiopathy cases. Mol. Med. 3, 695–707 (1997).

    Article  CAS  Google Scholar 

  32. Johnson-Wood, K. et al. Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer disease. Proc. Natl. Acad. Sci. USA 94, 1550–1555 (1997).

    Article  CAS  Google Scholar 

  33. Masliah, E. et al. Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F β-amyloid precursor protein and Alzheimer's disease. J. Neurosci. 16, 5795–5811 (1996).

    Article  CAS  Google Scholar 

  34. Paxinos, G. The Rat Nervous System. 2nd edn. (Academic, San Diego, 1995).

    Google Scholar 

  35. Mann, D.M. et al. Predominant deposition of amyloid-β 42(43) in plaques in cases of Alzheimer's disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene. Am. J. Pathol. 148, 1257–1266 (1996).

    CAS  PubMed  Google Scholar 

  36. Kuo, Y.-M. et al. Comparative analysis of Aβ chemical structure and amyloid plaque morphology of transgenic mice and alzheimer disease brains. J. Biol. Chem. (in the press).

  37. Weller, R.O. et al. Cerebral amyloid angiopathy. Amyloid β accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am. J. Pathol. 153, 725–733 (1998).

    Article  CAS  Google Scholar 

  38. Border, W.A. & Noble, N.A. TGF-β in kidney fibrosis: A target for gene therapy. Kidney Int. 51, 1388–1396 (1997).

    Article  CAS  Google Scholar 

  39. Galbreath, E., Kim, S.-J., Park, K., Brenner, M. & Messing, A. Overexpression of TGF-β1 in the central nervous system of transgenic mice results in hydrocephalus. J. Neuropathol. Exp. Neurol. 54, 339–349 (1995).

    Article  CAS  Google Scholar 

  40. Kisilevsky, R. Proteoglycans and other basement membrane proteins in amyloidoses. Mol. Neurobiol. 9, 23–24 (1994).

    Article  CAS  Google Scholar 

  41. Calhoun, M.E. et al. Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc. Natl. Acad. Sci. USA 96, 14088–14093 (1999).

    Article  CAS  Google Scholar 

  42. Verbeek, M.M., Otte-Höller, I., Veerhuis, R., Ruiter, D.J. & De Waal, R.M.W. Distribution of Aβ-associated proteins in cerebrovascular amyloid of Alzheimer's disease. Acta. Neuropathol. 96, 628–636 (1998).

    Article  CAS  Google Scholar 

  43. McGeer, P.L. & McGeer, E.G. Inflammation of the brain in Alzheimer's disease: Implications for therapy. J. Leukocyte Biol. 65, 409–415 (1999).

    Article  CAS  Google Scholar 

  44. Olichney, J.M. et al. The apolipoprotein E4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant. Neurology 47, 190–196 (1996).

    Article  CAS  Google Scholar 

Download references

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.).

Author information

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

Authors
  1. Tony Wyss-Coray
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carol Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fengrong Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gui-Qiu Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michelle Rohde
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lisa McConlogue
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eliezer Masliah
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lennart Mucke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tony Wyss-Coray.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/87945

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing