Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

Cotto, Bianca; Natarajaseenivasan, Kalimuthusamy; Ferrero, Kimberly; Wesley, Leroy; Sayre, Matthew; Langford, Dianne

doi:10.1002/glia.23291

Cited by 28 publications

(32 citation statements)

References 60 publications

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“…In particular, lncRNA-U1 significantly decreased BAG3 and BCL-2. This phenomenon is also in consistence with our earlier observation of Tat-induced BAG3 supression 55 . BAG3 is a molecular co-chaperone protein participates in apoptotic inhibition by binding to BCL-2 and forming an anti-apoptotic complex 56 , 57 .…”

Section: Discussionsupporting

confidence: 92%

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The lncRNA LOC102549805 (U1) modulates neurotoxicity of HIV-1 Tat protein

et al. 2020

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HIV-1 Tat is a potent neurotoxic protein that is released by HIV-1 infected cells in the brain and perturbs neuronal homeostasis, causing a broad range of neurological disorders in people living with HIV-1. Furthermore, the effects of Tat have been addressed in numerous studies to investigate the molecular events associated with neuronal cells survival and death. Here, we discovered that exposure of rat primary neurons to Tat resulted in the up-regulation of an uncharacterized long non-coding RNA (lncRNA), LOC102549805 (lncRNA-U1). Our observations showed that increased expression of lncRNA-U1 in neurons disrupts bioenergetic pathways by dysregulating homeostasis of Ca2+, mitigating mitochondrial oxygen reduction, and decreasing ATP production, all of which point mitochondrial impairment in neurons via the Tat-mediated lncRNA-U1 induction. These changes were associated with imbalances in autophagy and apoptosis pathways. Additionally, this study showed the ability of Tat to modulate expression of the neuropeptide B/W receptor 1 (NPBWR1) gene via up-regulation of lncRNA-U1. Collectively, our results identified Tat-mediated lncRNA-U1 upregulation resulting in disruption of neuronal homeostasis.

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Section: Discussionsupporting

confidence: 92%

“…After seven days, both groups of mice were sacrificed and brains were extracted/dissected into regions of interest (i.e. hippocampus, cerebellum, brain stem, and frontal cortex) 55 . Total RNA was isolated for each brain region using Trizole reagent (Invitrogen, ThermoFisher, Carlsbad, CA), as previously described 55 .…”

Section: Ethics Statementmentioning

confidence: 99%

The lncRNA LOC102549805 (U1) modulates neurotoxicity of HIV-1 Tat protein

et al. 2020

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“…Additional changes we noted uniquely in CA1 pyramidal neurons exposed to HIV-1 Tat include a decrease in whole cell capacitance and a likely directly associated decrease in the membrane time constant, which were observed absent any significant change in membrane resistance. While these effects are less obviously related to the clear trend toward hypoexcitability, it is interesting to note that there is some prior evidence that HIV-1 Tat can alter cholesterol production and lipid metabolism in hippocampal astrocytes and neurons (Cotto et al 2018;Mohseni Ahooyi et al 2018). Similarly, it is worth noting that several lines of evidence suggest that HIV-1 Tat may alter synaptodendritic structure and function via mechanisms that depend on filamentous actin (e.g., see Bertrand et al 2014;Festa et al 2015;Krogh et al 2015), a key cytoskeletal protein that may also be relevant to measurements of whole cell capacitance (Herring et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Region-specific effects of HIV-1 Tat on intrinsic electrophysiological properties of pyramidal neurons in mouse prefrontal cortex and hippocampus

Cirino

Harden

McLaughlin

et al. 2020

Journal of Neurophysiology

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Human immunodeficiency virus (HIV)-1 transactivator of transcription protein (Tat) is a viral protein that promotes transcription of the HIV genome and possesses cell-signaling properties. Long-term exposure of central nervous system (CNS) tissue to HIV-1 Tat is theorized to contribute to HIV-associated neurodegenerative disorder (HAND). In the current study, we sought to directly evaluate the effect of HIV-1 Tat expression on the intrinsic electrophysiological properties of pyramidal neurons located in layer 2/3 of the medial prefrontal cortex and in area CA1 of the hippocampus. Toward that end, we drove Tat expression with doxycycline (100 mg·kg−1·day−1 ip) in inducible Tat (iTat) transgenic mice for 7 days and then performed single-cell electrophysiological studies in acute tissue slices made through the prefrontal cortex and hippocampus. Control experiments were performed in doxycycline-treated G-tg mice, which retain the tetracycline-sensitive promoter but do not express Tat. Our results indicated that the predominant effects of HIV-1 Tat expression are excitatory in medial prefrontal cortical pyramidal neurons yet inhibitory in hippocampal pyramidal neurons. Notably, in these two populations, HIV-1 Tat expression produced differential effects on neuronal gain, membrane time constant, resting membrane potential, and rheobase. Similarly, we also observed distinct effects on action potential kinetics and afterhyperpolarization, as well as on the current-voltage relationship in subthreshold voltage ranges. Collectively, these data provide mechanistic evidence of complex and region-specific changes in neuronal physiology by which HIV-1 Tat protein may promote cognitive deficits associated with HAND. NEW & NOTEWORTHY We drove expression of human immunodeficiency virus (HIV)-1 transactivator of transcription protein (Tat) protein in inducible Tat (iTat) transgenic mice for 7 days and then examined the effects on the intrinsic electrophysiological properties of pyramidal neurons located in the medial prefrontal cortex (mPFC) and in the hippocampus. Our results reveal a variety of specific changes that promote increased intrinsic excitability of layer II/III mPFC pyramidal neurons and decreased intrinsic excitability of hippocampal CA1 pyramidal neurons, highlighting both cell type and region-specific effects.

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“…The use of cocaine increases the risk for becoming infected by HIV and many studies have shown that together, HIV and cocaine exacerbate neurocognitive impairment 31 . Moreover, 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 – 34 . In fact, cocaine promotes viral replication in infected astrocytes 15 .…”

Section: Introductionmentioning

confidence: 99%

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

Ahooyi

Shekarabi

Torkzaban

et al. 2018

Sci Rep

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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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Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

Cited by 28 publications

References 60 publications

The lncRNA LOC102549805 (U1) modulates neurotoxicity of HIV-1 Tat protein

The lncRNA LOC102549805 (U1) modulates neurotoxicity of HIV-1 Tat protein

Region-specific effects of HIV-1 Tat on intrinsic electrophysiological properties of pyramidal neurons in mouse prefrontal cortex and hippocampus

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

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