Human immunodeficiency virus 1 glycoprotein Gp120 induces amyloid pathology in neurons.

Abstract

The neuropathology of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) brains is similar to Alzheimer's disease brains in terms of an accumulation of the neurotoxic amyloid beta (Aβ) peptide. To test this hypothesis, we measured the levels of amyloid precursor protein (APP) and Aβ in HAND cerebrospinal fluid. We observed a 2-fold reduction in APP levels contrasted by an increase in Aβ in people living with HIV. However, the mechanism underlying these effects is challenging to elucidate. HIV may exert its neurotoxic effects in the CNS through the actions of the envelope glycoprotein gp120. Therefore, we exposed rat cortical neurons to this envelope protein. Neurons exposed to gp20 exhibited a morphological pathology as well as a 2-fold increase in the cellular levels of APP and Aβ42. The effect of gp120 was blocked by AMD3100, a CXCR4 antagonist. We then determined APP and Aβ levels in the hippocampus of aged gp120-transgenic (tg) mice, an animal model of HAND. Gp120 transgenic animals also exhibit a ~2-fold increase in APP and Aβ42 levels compared to wild type (WT). There was no change in APP mRNA, suggesting that the increase in Aβ42 could be due to APP processing. We then measured the hippocampal levels of beta-site APP cleaving enzyme-1 (BACE-1), and presenilin 1 and 2, nicastrin, and anterior pharynx defective 1 (APH1), components of the gamma secretase complex, in WT and gp120tg mice. We observed no significant changes in BACE1 levels; however, presenilin 1 levels were significantly increased, whereas nicastrin levels were significantly decreased in gp120 tg mice. Together, our data suggest that gp120 may be an important mechanism contributing to Aβ accumulation in HAND. This research advances our understanding of the mechanisms contributing to HAND, and establishes a novel mechanism for gp120 neurotoxicity involving the production of toxic protein.