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Dysregulation of Neuronal Cholesterol Homeostasis upon Exposure to HIV-1 Tat and Cocaine Revealed by RNA-Sequencing

Mohseni Ahooyi, T
; 
Shekarabi, M
; 
Torkzaban, B
; 
Langford, TD
; 
Burdo, TH
; 
Gordon, J
; 
Datta, PK
; 
Amini, S
; 
Khalili, K
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Genre
Journal Article
Date
2018-12-01
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Department
Subject
AIDS Dementia Complex
 Animals
 Biosynthetic Pathways
 Cells, Cultured
 Cholesterol
 Cocaine
 Cocaine-Related Disorders
 Computational Biology
 Disease Models, Animal
 Gene Expression Profiling
 HIV-1
 Hippocampus
 Humans
 Lipid Metabolism
 Macaca mulatta
 Mice
 Mice, Transgenic
 Neurons
 Primary Cell Culture
 Rats
 Sequence Analysis, RNA
 tat Gene Products, Human Immunodeficiency Virus
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http://hdl.handle.net/20.500.12613/4379
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DOI
10.1038/s41598-018-34539-9
Abstract
© 2018, The Author(s). HIV-1 Tat protein is released from HIV-1-infected cells and can enter non-permissive cells including neurons. Tat disrupts neuronal homeostasis and may contribute to the neuropathogenesis in people living with HIV (PLWH). The use of cocaine by PLWH exacerbates neuronal dysfunction. Here, we examined the mechanisms by which Tat and cocaine facilitate alterations in neuronal homeostatic processes. Bioinformatic interrogation of the results from RNA deep sequencing of rat hippocampal neurons exposed to Tat alone indicated the dysregulation of several genes involved in lipid and cholesterol metabolism. Following exposure to Tat and cocaine, the activation of cholesterol biosynthesis genes led to increased levels of free cholesterol and cholesteryl esters in rat neurons. Results from lipid metabolism arrays validated upregulation of several processes implicated in the biogenesis of β-amyloid and Alzheimer’s disease (AD), including sterol o-acyltransferase 1/acetyl-coenzyme A acyltransferase 1 (SOAT1/ACAT1), sortilin-related receptor L1 (SORL1) and low-density lipoprotein receptor-related protein 12 (LRP12). Further studies in Tat-treated primary neuronal cultures and brain tissues from HIV-1 transgenic mice as well as SIV-infected macaques confirmed elevated levels of SOAT1/ACAT 1 proteins. Our results offer novel insights into the molecular events involved in HIV and cocaine-mediated neuronal dysfunction that may also contribute to neuropathogenic events associated with the development of AD.
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Springer Science and Business Media LLC
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Scientific Reports
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