Sex-specific neurogenic deficits and neurocognitive disorders in middle-aged HIV-1 Tg26 transgenic mice

Putatunda, Raj; Zhang, Yonggang; Li, Fang; Fagan, Philip Regis; Zhao, Huaqing; Ramirez, Servio H.; Praticò, Domenico; Barbe, Mary F.; Hu, Wenhui

doi:10.1016/j.bbi.2019.04.029

Cited by 21 publications

(31 citation statements)

References 113 publications

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“…Although IFNAR1 deficiency resulted in a more pronounced neuroprotective effect in female HIVgp120tg mice compared to males, we observed that p38 MAPK and ERK play critical roles in neuronal injury that seem to be sexindependent. Of note, HIVgp120tg females displayed impaired recognition memory, via mechanisms that are incompletely understood, this finding is in line with previous work in HIV-1 Tg26 transgenic mice, a HIV-1 transgenic rat, and HIVgp120tg mice [58,67,68]. The impact of sex on neuroprotection observed here emphasizes the importance of understanding sexual dimorphism in HAND in order to develop new therapeutic approaches.…”

Section: Sexsupporting

confidence: 89%

A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1

Singh

Ojeda-Juárez

Maung

et al. 2020

J Neuroinflammation

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Background: HIV-1 infection remains a major public health concern despite effective combination antiretroviral therapy (cART). The virus enters the central nervous system (CNS) early in infection and continues to cause HIVassociated neurocognitive disorders (HAND). The pathogenic mechanisms of HIV-associated brain injury remain incompletely understood. Since HIV-1 activates the type I interferon system, which signals via interferon-α receptor (IFNAR) 1 and 2, this study investigated the potential role of IFNAR1 in HIV-induced neurotoxicity. Methods: We cross-bred HIVgp120-transgenic (tg) and IFNAR1 knockout (IFNAR1KO) mice. At 11-14 months of age, we performed a behavioral assessment and subsequently analyzed neuropathological alterations using deconvolution and quantitative immunofluorescence microscopy, quantitative RT-PCR, and bioinformatics. Western blotting of brain lysates and an in vitro neurotoxicity assay were employed for analysis of cellular signaling pathways. Results: We show that IFNAR1KO results in partial, sex-dependent protection from neuronal injury and behavioral deficits in a transgenic model of HIV-induced brain injury. The IFNAR1KO rescues spatial memory and ameliorates loss of presynaptic terminals preferentially in female HIVgp120tg mice. Similarly, expression of genes involved in neurotransmission reveals sex-dependent effects of IFNAR1KO and HIVgp120. In contrast, IFNAR1-deficiency, independent of sex, limits damage to neuronal dendrites, microgliosis, and activation of p38 MAPK and restores ERK activity in the HIVgp120tg brain. In vitro, inhibition of p38 MAPK abrogates neurotoxicity caused similarly by blockade of ERK kinase and HIVgp120. Conclusion: Our findings indicate that IFNAR1 plays a pivotal role in both sex-dependent and independent processes of neuronal injury and behavioral impairment triggered by HIV-1.

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Section: Sexsupporting

confidence: 89%

A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1

Singh

Ojeda-Juárez

Maung

et al. 2020

J Neuroinflammation

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“…These findings are indicative of hippocampal synaptic plasticity deficits in male Tg26 mice (Maren, Phan, & Liberzon, 2013). In accordance, a recent study of middle-aged Tg26 mice reported spatial memory deficits, although episodic memory was not affected at that age (Putatunda et al, 2019). We demonstrated that the contextual fear memory deficits in male Tg26 mice were not associated with changes in number of hippocampal neurons or microglia.…”

Section: Discussionsupporting

confidence: 90%

Glycogen synthase kinase‐3 inhibition rescues sex‐dependent contextual fear memory deficit in human immunodeficiency virus‐1 transgenic mice

Moidunny

Benneyworth

Titus

et al. 2020

British J Pharmacology

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Background and Purpose: A significant number of HIV-1 patients on antiretroviral therapy develop HIV-associated neurocognitive disorders (HAND). Evidence indicate that biological sex may regulate HAND pathogenesis, but the mechanisms remain unknown. We investigated synaptic mechanisms associated with sex differences in HAND, using the HIV-1-transgenic 26 (Tg26) mouse model. Experimental Approach: Contextual-and cue-dependent memories of male and female Tg26 mice and littermate wild type mice were assessed in a fear conditioning paradigm. Hippocampal electrophysiology, immunohistochemistry, western blot, qRT-PCR and ELISA techniques were used to investigate cellular, synaptic and molecular impairments. Key Results: Cue-dependent memory was unaltered in male and female Tg26 mice, when compared to wild type mice. Male, but not female, Tg26 mice showed deficits in contextual fear memory. Consistently, only male Tg26 mice showed depressed hippocampal basal synaptic transmission and impaired LTP induction in area CA1. These deficits in male Tg26 mice were independent of hippocampal neuronal loss and microglial activation but were associated with increased HIV-1 long terminal repeat mRNA expression, reduced hippocampal synapsin-1 protein, reduced BDNF mRNA and protein, reduced AMPA glutamate receptor (GluA1) phosphorylation levels and increased glycogen synthase kinase 3 (GSK3) activity. Importantly, selective GSK3 inhibition using 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione increased levels of synapsin-1, BDNF and phosphorylated-GluA1 proteins, restored hippocampal basal

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“…HIV-1 infection increases expression of inflammatory markers (TLR4, TNF-a, and NF-κB) and upregulates Sur1 and Trpm4 in astrocytes of Tg26 mouse brain tissues. The goal of this experiment was to evaluate the impact of HIV-1 infection on neuroinflammation in the brains of Tg26 mice, which represent a cART-relevant HIV mouse model whose pathological presentation resembles many aspects of HAND (22)(23)(24). Immunohistochemistry (IHC) was used to detect host innate immune proinflammatory responses and the expression of the Sur1-Trpm4 channel.…”

Section: Resultsmentioning

confidence: 99%

HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes

Makar

Gerzanich

et al. 2020

mBio

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Successful treatment of HIV-infected patients with combinational antiretroviral therapies (cART) can now prolong patients’ lives to nearly normal life spans. However, the new challenge faced by many of those HIV-infected patients is chronic neuroinflammation and neurotoxicity that often leads to HIV-associated neurocognitive disorders (HAND). However, the mechanism of neuropathogenesis underlying HAND, especially in those who are under cART, is not well understood. HAND is typically characterized by HIV-mediated glial neuroinflammation and neurotoxicity. However, the severity of HAND does not always correlate with HIV-1 viral load but, rather, with the extent of glial activation, suggesting that other HIV-associated factors might contribute to HAND. HIV-1 viral protein R (Vpr) could be one of those viral factors because of its association with neuroinflammation and neurotoxicity. The objective of this study was to delineate the specific roles of HIV-1 infection and Vpr in the activation of neuroinflammation and neurotoxicity, and the possible relationships with the Sur1-Trpm4 channel that contributes to neuroinflammation and neuronal death. Here, we show that HIV-1 expression correlates with activation of proinflammatory markers (TLR4, TNF-α, and NF-κB) and the Sur1-Trpm4 channel in astrocytes of HIV-infected postmortem human and transgenic Tg26 mouse brain tissues. We further show that Vpr alone activates the same set of proinflammatory markers and Sur1 in a glioblastoma SNB19 cell line that is accompanied by apoptosis. The Sur1 inhibitor glibenclamide significantly reduced Vpr-induced apoptosis. Together, our data suggest that HIV-1 Vpr-induced proinflammatory response and apoptosis are mediated at least in part through the Sur1-Trpm4 channel in astrocytes. IMPORTANCE Effective antiretroviral therapies can now prolong patients’ lives to nearly normal life span. The current challenge faced by many HIV-infected patients is chronic neuroinflammation and neurotoxicity that contributes to HIV-associated neurocognitive disorders (HAND). We show here that the expression of HIV-1 infection and Vpr correlates with the activation of proinflammatory markers (Toll-like receptor 4 [TLR4], tumor necrosis factor alpha [TNF-α], and NF-κB) and the sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel in astrocytes of brain tissues. We further show that an FDA-approved Sur1 inhibitory drug called glibenclamide significantly ameliorates apoptotic astrocytic cell death caused by HIV-1 Vpr, which could potentially open the possibility of repurposing glibenclamide for treating HAND.

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Sex-specific neurogenic deficits and neurocognitive disorders in middle-aged HIV-1 Tg26 transgenic mice

Cited by 21 publications

References 113 publications

A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1

A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1

Glycogen synthase kinase‐3 inhibition rescues sex‐dependent contextual fear memory deficit in human immunodeficiency virus‐1 transgenic mice

HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes

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