Abstract
Deposition of amyloid-β plaques is increased in the brains of HIV-infected individuals, and the HIV transactivator of transcription (Tat) protein affects amyloidogenesis through several indirect mechanisms. Here, we investigated direct interactions between Tat and amyloid-β peptide. Our in vitro studies showed that in the presence of Tat, uniform amyloid fibrils become double twisted fibrils and further form populations of thick unstructured filaments and aggregates. Specifically, Tat binding to the exterior surfaces of the Aβ fibrils increases β-sheet formation and lateral aggregation into thick multifibrillar structures, thus producing fibers with increased rigidity and mechanical resistance. Furthermore, Tat and Aβ aggregates in complex synergistically induced neurotoxicity both in vitro and in animal models. Increased rigidity and mechanical resistance of the amyloid-β–Tat complexes coupled with stronger adhesion due to the presence of Tat in the fibrils may account for increased damage, potentially through pore formation in membranes.
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Acknowledgements
We thank M. Bachani for preparing the Tat protein stocks, K. Mather for preparing the neuronal cell cultures used in the adhesion imaging experiments and A. Savonenko (Johns Hopkins University School of Medicine) for providing the APP-PS1 mice. This work was supported by intramural funds from NINDS, NIH Z01-NS003130 to A.N.; E.M. was supported by NIH grant R01-AG005131; N.H. was supported by NIH grant R01-MH096636; and E.K.D. was supported by NIH Z01-EB000085.
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A.H. and A.N. conceived and designed the study. A.H. performed AFM, ThT bulk fluorescence and single-fibril and cell-adhesion experiments, and analyzed and interpreted data. M.A.B. performed the computer simulations. E.K. performed the CD measurements. J.S. performed neurotoxicity experiments. E.M. and A.F. performed the transgenic-mouse experiments and immunohistochemistry analysis of brain samples. M.-H.L. performed immunohistochemistry of the Tat-injected mouse brain samples. A.M.D. and N.H. performed the experiments on Tat-injected mice. E.K.D. contributed to and supervised AFM data acquisition. A.H., A.N. and M.A.B. wrote the paper, and all authors edited the manuscript.
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Hategan, A., Bianchet, M., Steiner, J. et al. HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity. Nat Struct Mol Biol 24, 379–386 (2017). https://doi.org/10.1038/nsmb.3379
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DOI: https://doi.org/10.1038/nsmb.3379
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