Neurotrophins prevent HIV Tat‐induced neuronal apoptosis via a nuclear factor‐κB (NF‐κB)‐dependent mechanism

• Published in: Journal of neurochemistry Vol. 78; no. 4; pp. 874 - 889
• Main Authors: Ramirez, Servio H., Sanchez, Joseph F., Dimitri, Christopher A., Gelbard, Harris A., Dewhurst, Stephen, Maggirwar, Sanjay B.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.08.2001; Blackwell
• Subjects: apoptosis; Bcl‐2; Biological and medical sciences; Human immunodeficiency virus 1; human immunodeficiency virus type 1; Human viral diseases; Infectious diseases; Medical sciences; neurotrophic factors; nuclear factor‐κB; Tat; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Neurotrophin; Immunopathology; Rat; Rodentia; Retroviridae; AIDS; Immune deficiency; Lentivirus; Infection; Virus; Vertebrata; Mammalia; Viral disease; Animal; Transcription factor NFκB; Human immunodeficiency virus; Mechanism of action; Apoptosis; Dementia
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2001.00467.x

HIV‐1 associated dementia is thought to be caused by neuronal damage and death in response to the production of soluble neurotoxic factors by virally infected mononuclear phagocytes. These neurotoxins include HIV‐1 Tat. The ability of neurotrophins to promote cell survival prompted us to examine whether neurotrophins might also be capable of opposing the pro‐apoptotic effects of Tat. Here, we show that Tat‐induced neuronal apoptosis in primary cultures of rat cerebellar granule cells and in neuronally differentiated human SK‐N‐MC cells is profoundly inhibited by brain‐derived neurotrophic factor, nerve growth factor and activity‐dependent neurotrophic factor nonamer peptide. These neurotrophins activated the transcription factor NF‐κB, and inhibition of NF‐κB activation using a super‐repressor IκB‐α mutant was found to block the survival‐promoting activity of the neurotrophins. Reporter gene assays and immunoblot experiments revealed that the neurotrophins also up‐regulated the expression of Bcl‐2, at both the transcriptional and protein levels. Overexpression of the super‐repressor IκB‐α mutant prevented this induction of Bcl‐2 expression. Moreover, overexpression of either Bcl‐2, alone, or the RelA subunit of NF‐κB, alone, protected neurons from Tat‐induced apoptosis. These findings suggest that the activation of NF‐κB by neurotrophic factors may promote survival of neurons exposed to Tat, via regulation of anti‐apoptotic genes including Bcl‐2.