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<p>Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder that is typified by the formation of senile plaques containing Aβ and neurofibrillary tangles containing tau in a hyperphosphorylated state. Celastrol, a natural compound, has proven effective in alleviating AD pathology by enhancing autophagy and reducing tau aggregates. The present study investigates the neuroprotective mechanisms of celastrol, with a particular focus on the participation of the transcription factor T-box transcription factor 21 (TBX21) and triggering receptor expressed on myeloid cells 2 (TREM2) in microglial cells. In AD mouse models, celastrol upregulated TBX21 and TREM2, suppressed phosphorylated tau and inflammatory cytokines, and restored neuronal viability. In vitro, celastrol-treated microglia enhanced neuronal survival under amyloid-beta (Aβ) stress, effects abolished by TBX21/TREM2 knockdown. Mechanistically, TBX21 directly bound the TREM2 promoter to regulate its expression. These findings identified the TBX21-TREM2 axis as a therapeutic target for AD.</p>

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Celastrol Ameliorated Alzheimer’s Disease in Mice by Enhancing TBX21/TREM2 Expression in Microglia and Inhibiting Tau Phosphorylation

  • 期刊论文

  • 发表日期：

    2025年3月26日

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  • Fanfan Cao,
  • Pan Zhang,
  • Yongbin Chi,
  • Ying Wang,
  • Limin Xu,
  • Denghai Zhang

摘要

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder that is typified by the formation of senile plaques containing Aβ and neurofibrillary tangles containing tau in a hyperphosphorylated state. Celastrol, a natural compound, has proven effective in alleviating AD pathology by enhancing autophagy and reducing tau aggregates. The present study investigates the neuroprotective mechanisms of celastrol, with a particular focus on the participation of the transcription factor T-box transcription factor 21 (TBX21) and triggering receptor expressed on myeloid cells 2 (TREM2) in microglial cells. In AD mouse models, celastrol upregulated TBX21 and TREM2, suppressed phosphorylated tau and inflammatory cytokines, and restored neuronal viability. In vitro, celastrol-treated microglia enhanced neuronal survival under amyloid-beta (Aβ) stress, effects abolished by TBX21/TREM2 knockdown. Mechanistically, TBX21 directly bound the TREM2 promoter to regulate its expression. These findings identified the TBX21-TREM2 axis as a therapeutic target for AD.