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<p>Metformin, a first-line drug used to treat type 2 diabetes mellitus (T2DM), also reduces neuroinflammation and improves motor and cognitive outcomes. Metformin binds to presenilin enhancer 2 (PEN2) and further enhances its therapeutic benefits. The mechanisms of HIV-associated neurocognitive disorders (HANDs) remain unclear. HIV-1 trans-activator of transcription (Tat) contributes to neurotoxicity in HAND. We revealed that PEN2 expression decreased markedly in HAND patients and Tat-infected microglia. Metformin (200&#xa0;µM) treatment significantly reduced Tat-induced decreases in cell viability, oxidative stress, the proinflammatory response and excessive glutamate and iNOS release and had neuroprotective effects. Tat subsequently increased NF-κB activity, which was prominently suppressed during treatment. In addition, PEN2 knockdown in microglia dramatically reversed the neuroprotective effect of metformin against Tat. Our findings indicate that metformin binds PEN2 and modulates microglia-mediated HIV-1 Tat neurotoxicity in HAND.</p>

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Metformin promotes PEN2 expression to attenuate microglia-mediated neurotoxicity induced by HIV-1 Tat

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月4日

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  • Ya Shen,
  • Tianli Xu,
  • Yezi Sun,
  • Kelun Zhang,
  • Xiaojun Cao,
  • Limin Shen,
  • Mengjie Tang

摘要

Metformin, a first-line drug used to treat type 2 diabetes mellitus (T2DM), also reduces neuroinflammation and improves motor and cognitive outcomes. Metformin binds to presenilin enhancer 2 (PEN2) and further enhances its therapeutic benefits. The mechanisms of HIV-associated neurocognitive disorders (HANDs) remain unclear. HIV-1 trans-activator of transcription (Tat) contributes to neurotoxicity in HAND. We revealed that PEN2 expression decreased markedly in HAND patients and Tat-infected microglia. Metformin (200 µM) treatment significantly reduced Tat-induced decreases in cell viability, oxidative stress, the proinflammatory response and excessive glutamate and iNOS release and had neuroprotective effects. Tat subsequently increased NF-κB activity, which was prominently suppressed during treatment. In addition, PEN2 knockdown in microglia dramatically reversed the neuroprotective effect of metformin against Tat. Our findings indicate that metformin binds PEN2 and modulates microglia-mediated HIV-1 Tat neurotoxicity in HAND.