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HIV-induced neuroinflammation inhibits oligodendrocyte maturation via glutamate-dependent activation of the PERK arm of the integrated stress response

GLIA, ISSN: 1098-1136, Vol: 69, Issue: 9, Page: 2252-2271
2021
  • 10
    Citations
  • 0
    Usage
  • 16
    Captures
  • 16
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    10
  • Captures
    16
  • Mentions
    16
    • News Mentions
      13
      • News
        13
    • Blog Mentions
      3
      • Blog
        3

Most Recent News

Penn Dental Medicine Study Shows How HIV Infection Impacts Brain's White Matter

PHILADELPHIA, June 18, 2021 /PRNewswire/ -- It's long been known that people living with HIV experience a loss of white matter in their brains. work

Article Description

Despite combined antiretroviral therapy (cART), HIV-associated neurocognitive disorder (HAND) affects 30–50% of HIV-positive patients. Importantly, persistent white matter pathologies, specifically corpus callosum thinning and disruption of white matter microstructures observed in patients with HAND despite viral control through cART, raise the possibility that HIV infection in the setting of suboptimal cART may perturb oligodendrocyte (OL) maturation, function and/or survival, influencing HAND persistence in the cART era. To examine the effect of HIV infection on OL maturation, we used supernatants of primary human monocyte-derived macrophages infected with HIV (HIV/MDMs) to treat primary cultures of rat oligodendrocyte precursor cells (OPCs) during their differentiation to mature OLs. Using immunostaining for lineage-specific markers, we found that HIV/MDMs significantly inhibited OPC maturation. Based on our previous studies, we examined the potential role of several signaling pathways, including ionotropic glutamate receptors and the integrated stress response (ISR), and found that AMPA receptors (AMPAR)/kainic acid (KA) receptors (KARs) mediated the HIV/MDMs-induced defect in OL maturation. We also found that the treatment of OPC cultures with glutamate or AMPAR/KAR agonists phenocopied this effect. Blocking ISR activation, specifically the PERK arm of the ISR, protected OPCs from HIV/MDMs-mediated inhibition of OL maturation. Further, while glutamate, AMPA, and KA activated the ISR, inhibition of AMPAR/KAR activation prevented ISR induction in OPCs and rescued OL maturation. Collectively, these data identify glutamate signaling via ISR activation as a potential therapeutic pathway to ameliorate white matter pathologies in HAND and highlight the need for further investigation of their contribution to cognitive impairment.

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