Activation of α7 nicotinic acetylcholine receptor ameliorates HIV-associated neurology and neuropathology

Abstract

HIV-associated neurocognitive disorders (HAND) in the era of combination antiretroviral therapy are primarily manifested as impaired behaviors, glial activation/neuroinflammation and compromised neuronal integrity, for which there are no effective treatments currently available. In the current study, we used doxycycline-inducible astrocyte-specific HIV Tat transgenic mice (iTat), a surrogate HAND model and determined effects of PNU-125096, a positive allosteric modulator of α7 nicotinic acetylcholine receptor (α7 nAChR) on Tat-induced behavioral impairments and neuropathologies. We showed that PNU-125096 treatment significantly improved locomotor, learning and memory deficits of iTat mice while inhibited glial activation and increased PSD-95 expression in the cortex and hippocampus of iTat mice. Using α7 nAChR knockout mice, we showed that α7 nAChR knockout eliminated the protective effects of PNU-125096 on iTat mice. In addition, we showed that inhibition of p38 phosphorylation by SB239063, a p38 MAPK-specific inhibitor exacerbated Tat neurotoxicity in iTat mice. Lastly, we used primary mouse cortical individual cultures and neuron-astrocytes co-cultures and in vivo staining of iTat mouse brain tissues and showed that glial activation was directly involved in the interplay among Tat neurotoxicity, α7 nAChR activation, and p38 MAPK signaling pathway. Taken together, these findings demonstrated for the first time that α7 nAChR activation led to protection against HAND and suggest that α7 nAChR modulator PNU-125096 hold significant promise for development of therapeutics for HAND.

Homomeric and Heteromeric α7 Nicotinic Acetylcholine Receptors in Health and Some Central Nervous System Diseases

“…Tat increased α7 nAChR expression in microglia and astrocytes but decreased α7 nAChR expression in neurons, and this ratio was reversed upon treatment with the α7 nAChR positive allosteric modulator (PAM) PNU-125096 (see below). PSD95, a major scaffolding protein with an important role in synapse formation, increased its expression in the hippocampus and cortex upon PAM treatment, suggesting that its recovery is a compensatory mechanism coincident with the observed improvements in cognitive, mnemonic, and locomotive functions [24]. A549 adenocarcinoma, U87MG human grade-IV astrocytoma, and GBM5 gli toma cells lines express α7 and α9/α10 nAChRs subunits [23,48].…”

“…Metabotropic signaling is usually observed after ligand binding to α7 nAChRs in many non-neuronal cells, such as immune cells, where α7 nAChRs modulate the release of cytokines. The role of α7 nAChRs in HIV-associated neurocognitive disorders (HAND) was recently demonstrated by Zhao and coworkers [24]. α7 nAChR activation improved locomotor activity, learning, and memory deficits in an inducible model of HAND that expresses the HIV soluble protein Tat.…”

“…The multiplicity of important roles played by nAChRs means that their dysfunction is related to various disease conditions, some of which are beyond their involvement in classic neurotransmission (see "volume transmission" below). The association of nAChRs with brain pathologies, such as glioblastoma and neuroAIDS, is increasingly being documented [23,24].…”

HIV Nef Expression Down-modulated GFAP Expression and Altered Glutamate Uptake and Release and Proliferation in Astrocytes

“…Over 37 million people worldwide are infected with HIV [1]. Introduction of combination antiretroviral therapy has extended the lifespan of HIV-infected individuals, leading to increased incidents of minor cognitive and motor dysfunction [2][3][4][5][6][7]. More than 50% of HIV-infected individuals exhibit some form of neurological symptom collectively known as neuroHIV [8][9][10].…”

“…More than 50% of HIV-infected individuals exhibit some form of neurological symptom collectively known as neuroHIV [8][9][10]. Hallmarks observed in neuroHIV include impairments in neurobehaviors (motor ability and memory) and neuropathology such as neuroinflammation, impaired neuronal integrity, and astrocytosis [4,5,11].…”