Abstract
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.
Highlights
Calcium signaling[16,17], apoptosis[18] and neurotransmission[19,20], the mechanisms by which Tat alters these processes to impair neuronal functioning remain poorly understood
Transgenic rats harboring the HIV-1 genome served as a useful model to study the impact of HIV-1 on the central nervous system (CNS), and assessing neurobehavioral changes caused by the virus[25,26,27]
Primary cells derived from rat embryonic day 18 (E18) hippocampal tissue is highly enriched in neurons and has served as an in vitro model for studying many neuronal biological functions including formation of synaptic contacts and connectivity[45]
Summary
Calcium signaling[16,17], apoptosis[18] and neurotransmission[19,20], the mechanisms by which Tat alters these processes to impair neuronal functioning remain poorly understood. Whether Tat alters the expression of specific processes impairing neuronal functioning that potentially contribute to molecular events associated with neurocognitive impairments, remains unknown. Numerous in vitro and in vivo studies have reported that in combination, Tat and cocaine disrupt signaling cascades in the CNS and that these changes significantly affect functioning of uninfected bystander cells[32,33,34]. Lipid and cholesterol homeostasis are tightly controlled in brain in general and neurons in particular[35,36] Impairment of this homeostasis has been widely linked to neurodegeneration and neurological disorders such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease, among others[37,38,39]. ART was reported to improve cholesterol efflux capacity in individual infected with HIV44
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