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. 2025 Jun 4.
doi: 10.1007/s13365-025-01263-w. Online ahead of print.

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

Ya Shen #  1 , Tianli Xu #  2 , Yezi Sun  1 , Kelun Zhang  2 , Xiaojun Cao  1 , Limin Shen  3 , Mengjie Tang  4
Affiliations

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

Ya Shen et al. J Neurovirol. .

Abstract

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.

Keywords: HAND Tat; Metformin; Neurotoxicity; PEN2.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. Competing interest: The authors declare no competing interests.

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References

    1. Abdi M et al (2021) Metformin therapy attenuates pro-inflammatory microglia by inhibiting NF-kappaB in cuprizone demyelinating mouse model of multiple sclerosis. Neurotox Res 39:1732–1746. https://doi.org/10.1007/s12640-021-00417-y - DOI - PubMed
    1. Barzilai N et al (2016) Metformin as a tool to target aging. Cell Metab 23:1060–1065. https://doi.org/10.1016/j.cmet.2016.05.011 - DOI - PubMed - PMC
    1. Bertrand L, Cho HJ, Toborek M (2019) Blood-brain barrier pericytes as a target for HIV-1 infection. Brain 142:502–511. https://doi.org/10.1093/brain/awy339 - DOI - PubMed - PMC
    1. Borjabad A et al (2011) Significant effects of antiretroviral therapy on global gene expression in brain tissues of patients with HIV-1-associated neurocognitive disorders. PLoS Pathog 7:e1002213. https://doi.org/10.1371/journal.ppat.1002213 - DOI - PubMed - PMC
    1. Borrajo A et al (2021) Important role of microglia in HIV-1 associated neurocognitive disorders and the molecular pathways implicated in its pathogenesis. Ann Med 53:43–69. https://doi.org/10.1080/07853890.2020.1814962 - DOI - PubMed

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