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

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.