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

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 (A?) accumulation in BMEC through Alpha7 nicotinic acetylcholine receptor (?7 nAChR). Both in vitro (human BMEC) (HBMEC) and in vivo (mice) models of BBB were used to dissect the role of ?7 nAChR in up-regulation of A? induced by gp120, METH and NT. A? release from and transport across HBMEC were significantly increased by these factors. Methyllycaconitine (MLA), an antagonist of ?7 nAChR, could efficiently block these pathogenic effects. Furthermore, our animal data showed that these factors could significantly increase the levels of A?, Tau and Ubiquitin C-Terminal Hydrolase L1 (UCHL1) in mouse cerebrospinal fluid (CSF) and A? in the mouse brains. These pathogenicities were significantly reduced by MLA, suggesting that ?7 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.

SUBMITTER: Liu L 

PROVIDER: S-EPMC5225415 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature