Up-regulation of the Neuronal Nicotinic Receptor α7 by HIV Glycoprotein 120

Abstract

Approximately 30 -50% of the >30 million HIV-infected subjects develop neurological complications ranging from mild symptoms to dementia. HIV does not infect neurons, and the molecular mechanisms behind HIV-associated neurocognitive decline are not understood. There are several hypotheses to explain the development of dementia in HIV ؉ individuals, including neuroinflammation mediated by infected microglia and neuronal toxicity by HIV proteins. A key protein associated with the neurological complications of HIV, gp120, forms part of the viral envelope and can be found in the CSF of infected individuals. HIV-1-gp120 interacts with several receptors including CD4, CCR5, CXCR4, and nicotinic acetylcholine receptors (nAChRs). However, the role of nAChRs in HIV-associated neurocognitive disorder has not been investigated. We studied the effects of gp120 IIIB on the expression and function of the nicotinic receptor ␣7 (␣7-nAChR). Our results show that gp120, through activation of the CXCR4 chemokine receptor, induces a functional up-regulation of ␣7-nAChRs. Because ␣7-nAChRs have a high permeability to Ca 2؉ , we performed TUNEL staining to investigate the effects of receptor up-regulation on cell viability. Our data revealed an increase in cell death, which was blocked by the selective antagonist ␣-bungarotoxin. The in vitro data are supported by RT-PCR and Western blot analysis, confirming a remarkable up-regulation of the ␣7-nAChR in gp120-transgenic mice brains. Specifically, ␣7-nAChR up-regulation is observed in mouse striatum, a region severely affected in HIV ؉ patients. In summary, CXCR4 activation induces up-regulation of ␣7-nAChR, causing cell death, suggesting that ␣7-nAChR is a previously unrecognized contributor to the neurotoxicity associated with HIV infection.

HIV gp120 Induces Mucus Formation in Human Bronchial Epithelial Cells through CXCR4/α7-Nicotinic Acetylcholine Receptors

“…Inhibitors of CXCR4 and α7-nAChRs suppressed gp120-induced mucus formation in NHBE cells, but the CXCR4 inhibitor did not block nicotine-induced mucus production (not shown), suggesting that α7-nAChRs are downstream of CXCR4 in the gp120-induced mucus formation in NHBE cells. More recently, binding of gp120 to CXCR4 was shown to upregulate the expression nAChRs in neuronal cells [40]. Together these results suggest that CXCR4 communicates with nAChRs in regulating biological functions, including mucus production.…”

Alpha7 nicotinic acetylcholine receptor is required for amyloid pathology in brain endothelial cells induced by Glycoprotein 120, methamphetamine and nicotine

“…Recent studies have revealed that α7 nAChR is a critical link between inflammation and neurodegeneration, which is closely associated with Alzheimer’s disease, might be a potential therapeutic target for the pathogenicities-caused by HIV-1 and drugs of abuse38. It has been shown that gp120 could up-regulate α7 nAChR, which is a previously unrecognized contributor to the neurotoxicity associated with HAND38.…”

“…Recent studies have revealed that α7 nAChR is a critical link between inflammation and neurodegeneration, which is closely associated with Alzheimer’s disease, might be a potential therapeutic target for the pathogenicities-caused by HIV-1 and drugs of abuse38. It has been shown that gp120 could up-regulate α7 nAChR, which is a previously unrecognized contributor to the neurotoxicity associated with HAND38. It has been shown that enhancing peptides (EPs) derived from the co-receptor binding region of gp120 could promptly accelerated the formation of amyloid fibrils through the EP-derived nanofibers and significantly enhance HIV-1 infection3940.…”

Mechanisms of Cognitive Aging in the HIV-Positive Adult

“…The gp120 molecule, a surface protein of the HIV virus capsule, has been shown to bind to the highly calcium permeable homomeric α7-nAChR [80], upregulating receptor production, leading to astrocyte death, and subsequent apoptosis of nearby neurons, particularly in the striatum [81]. Another group also showed that gp120 may facilitate the production of reactive oxygen species that increase apoptotic loss of dopamine neurons in the substantia nigra, causing some of the Parkinsonian-like motor impairments that are present in HAND [82].…”