Triggering receptor expressed on myeloid cells 2(TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta(Aβ)clearance in Alzheimer’s disease(AD).Energy metabo...Triggering receptor expressed on myeloid cells 2(TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta(Aβ)clearance in Alzheimer’s disease(AD).Energy metabolic reprogramming(EMR)in microglia induced by TREM2 presents therapeutic targets for cognitive impairment in AD.Jiawei Xionggui Decoction(JWXG)has demonstrated effectiveness in enhancing energy supply,protecting microglia,and mitigating cognitive impairment in APP/PS1 mice.However,the mechanism by which JWXG enhances Aβphagocytosis through TREM2-mediated EMR in microglia remains unclear.This study investigates how JWXG facilitates microglial phagocytosis and alleviates cognitive deficits in AD through TREM2-mediated EMR.Microglial phagocytosis was evaluated through immunofluorescence staining in vitro and in vivo.The EMR level of microglia was assessed using high-performance liquid chromatography(HPLC)and enzyme-linked immunosorbent assay(ELISA)kits.The TREM2/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxia-inducible factor-1α(HIF-1α)signaling pathway was analyzed using Western blotting in BV_(2) cells.TREM2^(−/−)BV_(2) cells were utilized for reverse validation experiments.The Aβburden,neuropathological features,and cognitive ability in APP/PS1 mice were evaluated using ELISA kits,immunohistochemistry(IHC),and the Morris water maze(MWM)test.JWXG enhanced both the phagocytosis of EMR disorder-BV_(2) cells(EMRD-BV_(2))and increased EMR levels.Notably,these effects were significantly reversed in TREM2^(−/−)BV_(2) cells.JWXG elevated TREM2 expression,adenosine triphosphate(ATP)levels,and microglial phagocytosis in APP/PS1 mice.Additionally,JWXG reduced Aβ-burden,neuropathological lesions,and cognitive deficits in APP/PS1 mice.In conclusion,JWXG promoted TREM2-induced EMR and enhanced microglial phagocytosis,thereby reducing Aβdeposition,improving neuropathological lesions,and alleviating cognitive deficits.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82074150 and 82274240)the Natural Science Foundation of Sichuan Province(No.2023NSFSC1779).
文摘Triggering receptor expressed on myeloid cells 2(TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta(Aβ)clearance in Alzheimer’s disease(AD).Energy metabolic reprogramming(EMR)in microglia induced by TREM2 presents therapeutic targets for cognitive impairment in AD.Jiawei Xionggui Decoction(JWXG)has demonstrated effectiveness in enhancing energy supply,protecting microglia,and mitigating cognitive impairment in APP/PS1 mice.However,the mechanism by which JWXG enhances Aβphagocytosis through TREM2-mediated EMR in microglia remains unclear.This study investigates how JWXG facilitates microglial phagocytosis and alleviates cognitive deficits in AD through TREM2-mediated EMR.Microglial phagocytosis was evaluated through immunofluorescence staining in vitro and in vivo.The EMR level of microglia was assessed using high-performance liquid chromatography(HPLC)and enzyme-linked immunosorbent assay(ELISA)kits.The TREM2/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxia-inducible factor-1α(HIF-1α)signaling pathway was analyzed using Western blotting in BV_(2) cells.TREM2^(−/−)BV_(2) cells were utilized for reverse validation experiments.The Aβburden,neuropathological features,and cognitive ability in APP/PS1 mice were evaluated using ELISA kits,immunohistochemistry(IHC),and the Morris water maze(MWM)test.JWXG enhanced both the phagocytosis of EMR disorder-BV_(2) cells(EMRD-BV_(2))and increased EMR levels.Notably,these effects were significantly reversed in TREM2^(−/−)BV_(2) cells.JWXG elevated TREM2 expression,adenosine triphosphate(ATP)levels,and microglial phagocytosis in APP/PS1 mice.Additionally,JWXG reduced Aβ-burden,neuropathological lesions,and cognitive deficits in APP/PS1 mice.In conclusion,JWXG promoted TREM2-induced EMR and enhanced microglial phagocytosis,thereby reducing Aβdeposition,improving neuropathological lesions,and alleviating cognitive deficits.
基金supported by the National Natural Science Foundation of China (No. 81601228)Hubei Provincial Natural Science Foundation Innovation and Development Joint Fund Project of China (No. 2024AFD242)the Major Programs of Universities of Philosophy and Social Science (No. 23ZD165)。
