Neurotrophins prevent HIV Tat-induced neuronal apoptosis via a nuclear factor-kappa B (NF-kappa B)-dependent mechanism

HIV-1 associated dementia is thought to be caused by neuronal damage and de ath in response to the production of soluble neurotoxic factors by virally infected mononuclear phagocytes. These neurotoxins Include HIV-1 Tat. The a bility of neurotrophins to promote cell survival prompted us to examine whe ther neurotrophins might also be capable of opposing the pro-apoptotic effe cts of Tat. Here, we show that Tat-induced neuronal apoptosis in primary cu ltures of rat cerebellar granule cells and in neuronally differentiated hum an SK-N-MC cells is profoundly inhibited by brain-derived neurotrophic fact or, nerve growth factor and activity-dependent neurotrophic factor nonamer peptide. These neurotrophins activated the transcription factor NF-kappaB, and inhibition of NF-alphaB activation using a super-repressor I kappaB-alp ha mutant was found to block the survival-promoting activity of the neurotr ophins. Reporter gene assays and immunoblot experiments revealed that the n eurotrophins also up-regulated the expression of Bcl-2, at both the transcr iptional and protein levels. Overexpression of the super-repressor I kappaB -alpha mutant prevented this induction of Bcl-2 expression. Moreover, overe xpression of either Bcl-2, alone, or the RelA subunit of NF-kappaB, alone, protected neurons from Tat-induced apoptosis. These findings suggest that t he activation of NF-kappaB by neurotrophic factors may promote survival of neurons exposed to Tat, via regulation of anti-apoptotic genes including Bc l-2.