HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity

Alina Hategan, Mario A. Bianchet, Joseph P. Steiner, Elena Karnaukhova, Eliezer Masliah, Adam Fields, Myoung Hwa Lee, Alex M. Dickens, Norman Haughey, Emilios K. Dimitriadis, Avindra Nath

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalNature Structural and Molecular Biology
DOIs
StateAccepted/In press - Feb 20 2017

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Hategan, A., Bianchet, M. A., Steiner, J. P., Karnaukhova, E., Masliah, E., Fields, A., Lee, M. H., Dickens, A. M., Haughey, N., Dimitriadis, E. K., & Nath, A. (Accepted/In press). HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity. Nature Structural and Molecular Biology. https://doi.org/10.1038/nsmb.3379