title: HIV-1 Tat causes apoptotic death and calcium homeostasis alterations in rat neurons.
abstract: We investigated the role of the HIV-1 protein Tat in AIDS-associated dementia, by studying its toxicity on rat cortical and hippocampal neurons in vitro. We evaluated the involvement of astroglial cells and of caspase transduction pathway in determining Tat toxicity. Here we report that synthetic Tat(1-86) induced apoptotic death on cultured rat neurons in a time-dependent manner that was not influenced by glial coculture, and that was abolished by blocking caspase transduction pathway. A microfluorimetric analysis on the Tat excitatory properties on neurons, and its effect on intracellular calcium concentrations, revealed that Tat(1-86) induced increase in cytoplasmic free calcium concentrations in rat hippocampal and cortical neurons. This effect required extracellular calcium and was differently reduced by voltage dependent calcium channel blockers and both NMDA and non-NMDA glutamate receptors antagonists. Furthermore, we observed that Tat(1-86)-treated neurons showed increased sensitivity to the glutamate excitotoxicity. Thus, the Tat-induced neuronal injury seems to occur through a direct interaction of the protein with neurons, requires activation of caspases, and is likely to derive from Tat(1-86)-induced calcium loads and disruption of glutamatergic transmission.
authors.affiliation: Pharmacology and Neuroscience, National Cancer Research Institute, c/o Advanced Biotechnology Center, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Bonavia
authors.forename: A
authors.initials: A
authors.lastname: Bajetto
authors.forename: S
authors.initials: S
authors.lastname: Barbero
authors.forename: A
authors.initials: A
authors.lastname: Albini
authors.forename: D M
authors.initials: DM
authors.lastname: Noonan
authors.forename: G
authors.initials: G
authors.lastname: Schettini
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D015696:Gene Products, tat / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015696:Gene Products, tat; D002118:Calcium