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Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo

Nature Cell Biology volume 9, pages 139–148 (2007)Cite this article

Abstract

Hyperphosphorylated forms of the microtubule-associated protein (MAP) tau accumulate in Alzheimer's disease and related tauopathies and are thought to have an important role in neurodegeneration. However, the mechanisms through which phosphorylated tau induces neurodegeneration have remained elusive. Here, we show that tau-induced neurodegeneration is associated with accumulation of filamentous actin (F-actin) and the formation of actin-rich rods in Drosophila and mouse models of tauopathy. Importantly, modulating F-actin levels genetically leads to dramatic modification of tau-induced neurodegeneration. The ability of tau to interact with F-actin in vivo and in vitro provides a molecular mechanism for the observed phenotypes. Finally, we show that the Alzheimer's disease-linked human β-amyloid protein (Aβ) synergistically enhances the ability of wild-type tau to promote alterations in the actin cytoskeleton and neurodegeneration. These findings raise the possibility that a direct interaction between tau and actin may be a critical mediator of tau-induced neurotoxicity in Alzheimer's disease and related disorders.

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Figure 1: Interaction between tau and the actin cytoskeleton induces abnormal F-actin bundling and accumulation.
Figure 2: Actin-rich rod formation accompanies neurodegeneration in the brains of tau transgenic flies and mice.
Figure 3: Changes in F-actin modulate neurotoxicity in the retina of tau transgenic flies.
Figure 4: F-actin accumulation and actin-rich rod formation correlate with the degree of tau-induced neuronal degeneration.
Figure 5: Changes in the actin cytoskeleton occur downstream of tau phosphorylation.
Figure 6: Aβ and tau interact in a synergistic manner to promote actin-rich rod formation and neuronal degeneration.

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Acknowledgements

We are grateful to those who generously sent us stocks and reagents (see Methods). Fly injection services were provided by D. Rennie at the Cutaneous Biology Research Center at Massachusetts General Hospital. We thank R. Stearns for help with the SEM facility. The rTg4510 mice were provided by G. Carlson and K. Hsiao Ashe. This work was supported by National Institutes of Health (NIH) grants AG19790 and AG5134 and a McKnight Foundation grant to M.B.F. T.A.F is the recipient of a postdoctoral fellowship from The John Douglas French Alzheimer's Foundation.

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Authors and Affiliations

  1. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Harvard New Research Building Room 652, 77 Louis Pasteur Avenue, Boston, 02115, MA, USA

    Tudor A. Fulga, Ilan Elson-Schwab, Vikram Khurana, Michelle L. Steinhilb & Mel B. Feany

  2. Department of Neurology, Massachusetts General Hospital, Charlestown, 02129, MA, USA

    Tara L. Spires & Bradley T. Hyman

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Contributions

T.A.F., I.E.-S., V.K. and M.B.F. contributed to study design, data acquisition and manuscript preparation. M.L.S., T.L.S. and B.T.H. contributed critical reagents and assisted with data analysis.

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Correspondence to Tudor A. Fulga or Mel B. Feany.

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Fulga, T., Elson-Schwab, I., Khurana, V. et al. Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat Cell Biol 9, 139–148 (2007). https://doi.org/10.1038/ncb1528

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