Facilitating microglial phagocytosis by which Jiawei Xionggui decoction alleviates cognitive impairment via TREM2-mediated Energy metabolic reprogramming

TREM2-mediated microglial phagocytosis is an energy-intensive process, and plays an important role in the clearance of amyloid beta (Aβ) in Alzheimer's disease (AD). Energy metabolic reprogramming (EMR) in microglia induced by TREM2 provides therapeutic targets for cognitive impairment of AD. Jiawei Xionggui decoction (JWXG) has been demonstrated to enhance energy supply, microglia protection and cognitive impairment mitigation in APP/PS1 mice. However, it remains unclear whether JWXG can enhance phagocytosis of Aβ by modulating TREM2-mediated EMR in microglia. This study aims to elucidate the mechanism by which JWXG facilitates microglial phagocytosis, thus alleviating cognitive deficits in AD through TREM2-mediated EMR. The microglial phagocytosis was examined by immunofluorescence staining in vitro and in vivo. The EMR level of microglia was detected using HPLC and ELISA kits. Additionally, the TREM2/Akt/mTOR/HIF-1α signaling pathway was analyzed using Western blot in BV₂ cells. And the TREM2^-/- BV₂ cells were adopted for the reverse validation experiments. Finally, the Aβ burden, neuropathological features and cognitive ability in APP/PS1 mice were evaluated using ELISA kits, immunohistochemistry and Morris Water Maze test. JWXG not only enhanced the phagocytosis of energy metabolic reprogramming disorder-BV₂ cells (EMRD-BV₂), but also increased the EMR level. Interestingly, these effects of JWXG were significantly reversed in TREM2^-/- BV₂ cells. Coincidentally, JWXG elevated the TREM2 expression, ATP level, and the microglial phagocytosis in APP/PS1 mice. Furthermore, JWXG mitigated the Aβ-burden, neuropathological lesions, and cognitive deficits in APP/PS1 mice. So, JWXG promoted TREM2-induced EMR and rescued microglial phagocytosis, thereby reducing Aβ deposition, ameliorating neuropathological lesions, and alleviating cognitive deficits.