title: HIV-1 Tat-induced cerebrovascular toxicity is enhanced in mice with amyloid deposits.
abstract: HIV-1-infected brains are characterized by elevated depositions of amyloid beta (Aβ); however, the interactions between Aβ and HIV-1 are poorly understood. In the present study, we administered specific HIV-1 protein Tat into the cerebral vasculature of 50-52-week-old double transgenic (B6C3-Tg) mice that express a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) and are characterized by increased Aβ depositions in the brain. Exposure to Tat increased permeability across cerebral capillaries, enhanced disruption of zonula occludens (ZO)-1 tight junction protein, and elevated brain expression of matrix metalloproteinase-9 (MMP-9) in B6C3-Tg mice as compared with age-matched littermate controls. These changes were associated with increased leukocyte attachment and their transcapillary migration. The majority of Tat-induced effects were attenuated by treatment with a specific Rho inhibitor, hydroxyfasudil. The results of animal experiments were reproduced in cultured brain endothelial cells exposed to Aβ and/or Tat. The present data indicate that increased brain levels of Aβ can enhance vascular toxicity and proinflammatory responses induced by HIV-1 protein Tat.
authors.affiliation: Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Jeong June
authors.initials: JJ
authors.lastname: Choi
authors.forename: Yean Jung
authors.initials: YJ
authors.lastname: Choi
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hennig
authors.forename: Michal
authors.initials: M
authors.lastname: Toborek
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects / Q000503:physiopathology; D002561:Cerebrovascular Disorders / Q000139:chemically induced* / Q000503:physiopathology*; D015696:Gene Products, tat / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism*; D014657:Vasculitis / Q000139:chemically induced* / Q000503:physiopathology*
chemical_list: D016229:Amyloid beta-Peptides; D015696:Gene Products, tat