Facilitating microglial phagocytosis by which Jiawei Xionggui Decoction alleviates cognitive impairment via TREM2-mediated energy metabolic reprogramming
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Wen Wen1, Jie Chen1, Junbao Xiang1
1State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Institute of Material Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Abstract:
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 Aβ phagocytosis 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 BV2 cells. TREM2-/- BV2 cells were utilized for reverse validation experiments. The Aβ burden, 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-BV2 cells (EMRD-BV2) and increased EMR levels. Notably, these effects were significantly reversed in TREM2-/- BV2 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 Aβ deposition, improving neuropathological lesions, and alleviating cognitive deficits.
Insights
Jiawei Xionggui Decoction (JWXG) enhances amyloid beta (Aβ) clearance in Alzheimer's disease (AD) by boosting microglial phagocytosis via TREM2-mediated energy metabolic reprogramming (EMR). This treatment improves cognitive function and reduces AD pathology in mice.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Microglial phagocytosis, crucial for amyloid beta (Aβ) clearance in Alzheimer's disease (AD), is an energy-intensive process mediated by Triggering Receptor Expressed on Myeloid cells 2 (TREM2).
- Energy metabolic reprogramming (EMR) in microglia, influenced by TREM2, represents a potential therapeutic target for AD-related cognitive impairment.
- Jiawei Xionggui Decoction (JWXG) has shown promise in improving energy supply and mitigating cognitive deficits in AD models, but its precise mechanism remains elusive.
Purpose of the Study:
- To investigate the mechanism by which JWXG enhances Aβ phagocytosis through TREM2-mediated EMR in microglia.
- To evaluate the therapeutic effects of JWXG on microglial phagocytosis, EMR, and cognitive function in an AD mouse model.
Main Methods:
- Microglial phagocytosis was assessed using immunofluorescence staining in vitro and in vivo.
- EMR levels were quantified via high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA).
- The TREM2/Akt/mTOR/HIF-1α pathway was analyzed by Western blotting, and TREM2 knockout cells were used for validation. AD mice (APP/PS1) underwent behavioral tests (Morris water maze), and Aβ burden/neuropathology were assessed via ELISA and immunohistochemistry (IHC).
Main Results:
- JWXG treatment significantly enhanced phagocytosis and EMR levels in microglia, effects that were dependent on TREM2 expression.
- In APP/PS1 mice, JWXG increased TREM2 expression, adenosine triphosphate (ATP) levels, and microglial phagocytosis.
- JWXG administration led to reduced Aβ burden, neuropathological lesions, and improved cognitive performance in APP/PS1 mice.
Conclusions:
- JWXG promotes TREM2-induced EMR, thereby enhancing microglial phagocytosis.
- This enhancement of microglial function by JWXG contributes to the reduction of Aβ deposition and neuropathological damage.
- JWXG effectively alleviates cognitive deficits in an AD mouse model, highlighting its therapeutic potential.
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