Abstract
One of the most challenging issues in HIV-associated neurocognitive disorders (HAND) caused by HIV-1 virotoxins and drug abuse is the lack of understanding the underlying mechanisms that are commonly associated with disorders of the blood-brain barrier (BBB), which mainly consists of brain microvascular endothelial cells (BMEC). Here, we hypothesized that Glycoprotein 120 (gp120), methamphetamine (METH) and nicotine (NT) can enhance amyloid-beta (Aβ) accumulation in BMEC through Alpha7 nicotinic acetylcholine receptor (α7 nAChR). Both in vitro (human BMEC) (HBMEC) and in vivo (mice) models of BBB were used to dissect the role of α7 nAChR in up-regulation of Aβ induced by gp120, METH and NT. Aβ release from and transport across HBMEC were significantly increased by these factors. Methyllycaconitine (MLA), an antagonist of α7 nAChR, could efficiently block these pathogenic effects. Furthermore, our animal data showed that these factors could significantly increase the levels of Aβ, Tau and Ubiquitin C-Terminal Hydrolase L1 (UCHL1) in mouse cerebrospinal fluid (CSF) and Aβ in the mouse brains. These pathogenicities were significantly reduced by MLA, suggesting that α7 nAChR may play an important role in neuropathology caused by gp120, METH and NT, which are the major pathogenic factors contributing to the pathogenesis of HAND.
Highlights
Have been shown to be neurotoxic since they could mediate inflammation and oxidative stress[8]
One of the most challenging issues in HIV-associated neurocognitive disorders (HAND) caused by HIV-1 virotoxins [e.g., Glycoprotein 120(gp120)] and related comorbid factors [e.g., methamphetamine (METH) and nicotine (NT)] is the lack of understanding the underlying mechanisms of the shared comorbidities that are commonly associated with disorders of the blood-brain barrier (BBB), which mainly consists of brain microvascular endothelial cells (BMEC)
Our recent study suggests that alpha[7] nicotinic acetylcholine receptor (α7 nAChR) is an essential regulator of inflammation, which contributes to neuroinflammation and BBB disorders caused by microbial (e.g., HIV-1 Glycoprotein 41(gp41)/gp[120], Cryptococcus neoforman, E. coli) and non-microbial (e.g., METH and nicotine) factors[10,11,12]
Summary
HIV-1 gp[120], METH and NT exposure increases Aβ levels of the culture supernatants in human BMECs (HBMECs). Furthermor, the numbers of SA β-gal stained cells were significantly lower in both the control group with treatment and MLA-treated cells exposed to HIV-1 gp[120], METH and NT (Fig. 8B) These results suggest that the α7 antagonist MLA suppresses HIV-1 gp120-, METH- and NT-induced senescence in HBMECs. Cerebrospinal fluid (CSF) levels of biomarkers for Alzheimer’s-like brain pathology and BBB injury are reduced by chemical blockage of α7 nAChR (MLA) upon exposure to HIV-1 gp[120], METH and NT. The current study showed that nicotine could upregulateα[7] nAChR through activation of RAGE and S100B in the dentate gyrus (DG) of the hippocampus upon exposure to gp[120], METH or NT in vivo, the decrease of α7 nAChR and RAGE alleviated leukocyte (HL60 cell) transmigration across the HBMEC monolayers These findings suggest that α7 nAChR is required for the modulation of inflammatory response through the cholinergic pathway, which may be involved in the pathogenesis of CNS comorbidities caused by HIV-1 virotoxins (e.g., gp120) and related factors (e.g., nicotine and METH). Further insight into how HIV-1, METH and NT utilize the host cholinergic α7 nAChR pathway to augment their virulence capacity will advance our understanding of the pathogenesis and therapeutics of CNS disorders caused by multiple comorbidities
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