Neurodegenerative effects of recombinant HIV-1 Tat(1-86) are associated with inhibition of microtubule formation and oxidative stress-related reductions in microtubule-associated protein-2(a,b).
The human immunodeficiency virus 1 (HIV-1) protein Trans-activator of Transcription (Tat) is a nuclear regulatory protein that may contribute to the development of HIV-1 associated dementia by disrupting the neuronal cytoskeleton. The present studies examined effects of recombinant Tat(1-86; 1-100 nM) on microtubule-associated protein (MAP)-dependent and MAP-independent microtubule formation ex vivo and oxidative neuronal injury in rat organotypic hippocampal explants. Acute exposure to Tat(1-86) (≥1 nM) markedly reduced MAP-dependent and -independent microtubule formation ex vivo, as did vincristine sulfate (0.1-10 μM). Cytotoxicity, as measured by propidium iodide uptake, was observed in granule cells of the DG with exposure to 100 nM Tat(1-86) for 24 or 72 h, while significant reductions in MAP-2 immunoreactivity were observed in granule cells and pyramidal cells of the CA1 and CA3 regions at each timepoint. These effects were prevented by co-exposure to the soluble vitamin E analog Trolox (500 μM). Thus, effects of Tat(1-86) on the neuronal viability may be associated with direct interactions with microtubules and generation of oxidative stress.
Department of Psychology, University of Kentucky, B449 Biomedical and Biological Sciences Research Building, 741 South Limestone St., Lexington, KY 40536-0509, USA.
Tracy R
TR
Butler
Katherine J
KJ
Smith
Rachel L
RL
Self
Brittany B
BB
Braden
Mark A
MA
Prendergast
D000818:Animals; D002417:Cattle; D002839:Chromans / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D015696:Gene Products, tat / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology
D002839:Chromans; D015696:Gene Products, tat; D008869:Microtubule-Associated Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014404:Tubulin; D014750:Vincristine; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
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