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Restoring metabolism of microglia by dapsone rescues pathology and improves memory in a mouse model of Alzheimer’s disease

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作者

    Shufei Feng， 
    Shufei Feng
    • Peking University No.6 Hospital
    Nianzhuang Qiu， 
    Nianzhuang Qiu
    Tangsheng Lu， 
    Tangsheng Lu
    Lei Han， 
    Lei Han
    Zihang Li， 
    Zihang Li
    • Shandong Institute of Brain Science and Brain-inspired Research
    Siyu Liu， 
    Siyu Liu
    Liyuan Guo， 
    Liyuan Guo
    • Shandong Institute of Brain Science and Brain-inspired Research
    Chunxia Huang， 
    Chunxia Huang
    • Shandong Institute of Brain Science and Brain-inspired Research
    Lu Cao， 
    Lu Cao
    Xiaoxing Liu， 
    Xiaoxing Liu
    Jie Shi， 
    Jie Shi
    Qingqing Yin， 
    Qingqing Yin
    • Shandong Provincial Hospital Affiliated to Shandong First Medical University
    Furen Zhang， 
    Furen Zhang
    Yabin Wei， 
    Yabin Wei
    Lin Lu， 
    Lin Lu
    Kai Yuan
    Kai Yuan
分类
神经生物学
关键词
Alzheimer’s disease; Immunometabolism; Microglia

摘要

Alzheimer’s disease (AD) is characterized by progressive cognitive decline and neuropathological changes, with increasing evidence implicating dysregulated microglial immunometabolism in disease progression. Dapsone (DDS), a clinically approved anti-leprosy drug with reported anti-inflammatory and neuroprotective properties, has not yet been evaluated for its capacity to regulate microglial metabolism in AD. Here, using triple-transgenic AD mice (3×Tg-AD mice) and amyloid-β oligomer (oAβ)-challenged in vitro microglial models, we investigated the therapeutic effects and mechanisms of DDS in AD. Six-week oral DDS treatment improved hippocampus-dependent cognitive performance, reduced amyloid-β (Aβ) deposition and tau phosphorylation, and restored impaired hippocampal synaptic plasticity. DDS remodeled microglial morphology toward a homeostatic-like phenotype in 3×Tg-AD mice and enhanced the phagocytic uptake of Aβ and synaptosomes in oAβ-challenged microglia. Single-cell RNA sequencing revealed DDS associated remodeling of microglial transcriptional states, marked by enrichment of homeostatic and proteostasis related gene programs and attenuation of inflammatory microglial signatures. DDS restored microglial mitochondrial function and promoted microglial metabolic reprogramming from glycolysis toward mitochondrial respiration. DDS interacted with proline-rich Akt substrate of 40 kDa (PRAS40) and suppressed PRAS40-mTORC1 signaling. Consistently, DDS partially normalized hippocampal glycolytic and TCA cycle metabolism and improved cerebral glucose utilization in 3×Tg-AD mice. Microglia-specific PRAS40 overexpression attenuated the cognitive and pathological effects of DDS, whereas PRAS40 knockdown produced effects like DDS. In summary, DDS improves cognitive deficits and reduces AD pathology. Microglial PRAS40–mTORC1 signaling may contribute to these effects by regulating microglial metabolism. Targeting this pathway may provide a potential therapeutic strategy for AD.

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https://doi.org/10.65215/LTSpreprints.2026.07.12.000282

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2026-07-13

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Feng, S., Qiu, N., Lu, T., Han, L., Li, Z., Liu, S., Guo, L., Huang, C., Cao, L., Liu, X., Shi, J., Yin, Q., Zhang, F., Wei, Y., Lu, L., & Yuan, K. (2026). Restoring metabolism of microglia by dapsone rescues pathology and improves memory in a mouse model of Alzheimer’s disease. 浪淘沙预印本平台. https://doi.org/10.65215/LTSpreprints.2026.07.12.000282

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