title: HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity.
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.
authors.affiliation: Section of Infections of the Nervous System, National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Hategan
authors.affiliation: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.|Structural Enzymology and Thermodynamics Group, Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Mario A
authors.identifier: 0000-0001-9032-7549
authors.initials: MA
authors.lastname: Bianchet
authors.affiliation: Section of Infections of the Nervous System, National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Steiner
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Karnaukhova
authors.affiliation: Department of Pathology, University of California at San Diego, San Diego, California, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Department of Pathology, University of California at San Diego, San Diego, California, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Fields
authors.affiliation: Section of Infections of the Nervous System, National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Myoung-Hwa
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Dickens
authors.affiliation: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Norman
authors.initials: N
authors.lastname: Haughey
authors.affiliation: Scanning Probe Microscopy Unit, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Emilios K
authors.initials: EK
authors.lastname: Dimitriadis
authors.affiliation: Section of Infections of the Nervous System, National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000633:toxicity*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002942:Circular Dichroism; D005455:Fluorescent Antibody Technique; D006801:Humans; D008822:Mice, Transgenic; D018625:Microscopy, Atomic Force; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000737:chemistry / Q000633:toxicity*; D066329:Protein Aggregates / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D017207:Rats, Sprague-Dawley; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D066329:Protein Aggregates; D054322:tat Gene Products, Human Immunodeficiency Virus