Tetrahydroxy Stilbene Glycoside Reduces Abeta Deposition by Modulating Microglia Activation and via TREM2/PI3K/AKT Pathway in APP/PS1 Mice
Ming Li
Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorQihan Song
Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorShanshan Jie
Institute of Basic Theory of Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
Search for more papers by this authorChenchen Wang
Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorCan Zhang
Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorKexin Chi
Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorCorresponding Author
Yan Gao
Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Correspondence:
Yan Gao ([email protected])
Tianzuo Li ([email protected])
Search for more papers by this authorCorresponding Author
Tianzuo Li
Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Correspondence:
Yan Gao ([email protected])
Tianzuo Li ([email protected])
Search for more papers by this authorMing Li
Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorQihan Song
Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorShanshan Jie
Institute of Basic Theory of Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
Search for more papers by this authorChenchen Wang
Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorCan Zhang
Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorKexin Chi
Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorCorresponding Author
Yan Gao
Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Correspondence:
Yan Gao ([email protected])
Tianzuo Li ([email protected])
Search for more papers by this authorCorresponding Author
Tianzuo Li
Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Correspondence:
Yan Gao ([email protected])
Tianzuo Li ([email protected])
Search for more papers by this authorMing Li and Qihan Song authors are the first authors.
Yan Gao and Tianzuo Li contributed equally to this work.
BCPT recognizes the potential of natural product studies in the identification of new therapies but wishes to emphasize that findings based on uncharacterized mixtures of compounds are preliminary in nature and serve primarily as hypothesis generating to form the basis for more elaborate investigations.
Funding: This work was supported by the National Natural Science Foundation of China (No. 82271206, 82204645) and the Fund of Beijing Shijitan Hospital, Capital Medical University (2022-C02).
ABSTRACT
Tetrahydroxy stilbene glycoside (TSG), which is the primary active substance of Chinese herbal medicine called Polygonum multiflorum, has been acknowledged to alleviate Alzheimer's disease (AD)-induced learning disorder in the transgene mice. Because the microglia activation is really important during the AD progression, herein, we determined the effects of TSG on AD neuropathology, microglia polarization and its underlying mechanism. We used APP/PS1 mice along with immunohistochemistry and immunofluorescence techniques to evaluate the function of TSG as 60, 120 and 180 mg/kg on Aβ deposition, neuronal loss and microglia polarization induced by AD. Additionally, we assessed the effects of TSG on TREM2 signalling using both molecular docking and Western blot analysis. TSG was found to promote neuronal survival and decrease Aβ deposition in APP/PS1 mice. Moreover, TSG reduced microglia M1 polarization and modulated the TREM2/PI3K/AKT signalling pathways. TSG could reduce neuronal impairment by mediating the microglia polarization by TREM2/PI3K/AKT signalling pathway in APP/PS1 mice and is a latent pharmacological research direction for the therapy in the patients with AD.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
References
- 12021 Alzheimer's Disease Facts and Figures,” Alzheimers Dement 3 (2021): 327–406, https://doi.org/10.1002/alz.12328.
10.1002/alz.12328 Google Scholar
- 2C. A. Lane, J. Hardy, and J. M. Schott, “Alzheimer's Disease,” European Journal of Neurology 1 (2018): 59–70, https://doi.org/10.1111/ene.13439.
10.1111/ene.13439 Google Scholar
- 3D. Puzzo, W. Gulisano, A. Palmeri, and O. Arancio, “Rodent Models for Alzheimer's Disease Drug Discovery,” Expert Opinion on Drug Discovery 7 (2015): 703–711, https://doi.org/10.1517/17460441.2015.1041913.
10.1517/17460441.2015.1041913 Google Scholar
- 4L. Zuroff, D. Daley, K. L. Black, and M. Koronyo-Hamaoui, “Clearance of Cerebral Aβ in Alzheimer's Disease: Reassessing the Role of Microglia and Monocytes,” Cellular and Molecular Life Sciences 12 (2017): 2167–2201, https://doi.org/10.1007/s00018-017-2463-7.
10.1007/s00018-017-2463-7 Google Scholar
- 5M. Fakhoury, “Microglia and Astrocytes in Alzheimer's Disease: Implications for Therapy,” Current Neuropharmacology 5 (2018): 508–518, https://doi.org/10.2174/1570159x15666170720095240.
10.2174/1570159X15666170720095240 Google Scholar
- 6W. T. Chen, A. Lu, K. Craessaerts, et al., “Spatial Transcriptomics and in Situ Sequencing to Study Alzheimer's Disease,” Cell 4 (2020): 976–991, https://doi.org/10.1016/j.cell.2020.06.038.
10.1016/j.cell.2020.06.038 Google Scholar
- 7W. Feng, Y. Zhang, Z. Wang, et al., “Microglia Prevent Beta-Amyloid Plaque Formation in the Early Stage of an Alzheimer's Disease Mouse Model With Suppression of Glymphatic Clearance,” Alzheimer's Research & Therapy 12, no. 1 (2020): 125, https://doi.org/10.1186/s13195-020-00688-1.
- 8Q. Qin, Z. Teng, C. Liu, Q. Li, Y. Yin, and Y. Tang, “TREM2, Microglia, and Alzheimer's Disease,” Mechanisms of Ageing and Development 195 (2021): 111438, https://doi.org/10.1016/j.mad.2021.111438.
- 9C. Yunna, H. Mengru, W. Lei, and C. Weidong, “Macrophage M1/M2 Polarization,” European Journal of Pharmacology 877 (2020): 173090, https://doi.org/10.1016/j.ejphar.2020.173090.
- 10A. Shapouri-Moghaddam, S. Mohammadian, H. Vazini, et al., “Macrophage Plasticity, Polarization, and Function in Health and Disease,” Journal of Cellular Physiology 9 (2018): 6425–6440, https://doi.org/10.1002/jcp.26429.
10.1002/jcp.26429 Google Scholar
- 11Y. Tang and W. Le, “Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases,” Molecular Neurobiology 2 (2016): 1181–1194, https://doi.org/10.1007/s12035-014-9070-5.
10.1007/s12035-014-9070-5 Google Scholar
- 12S. Guo, H. Wang, and Y. Yin, “Microglia Polarization From M1 to M2 in Neurodegenerative Diseases,” Frontiers in Aging Neuroscience 14 (2022): 815347, https://doi.org/10.3389/fnagi.2022.815347.
- 13F. A. Sayed, L. Kodama, L. Fan, et al., “AD-Linked R47H-TREM2 Mutation Induces Disease-Enhancing Microglial States via AKT Hyperactivation,” Science Translational Medicine 13, no. 622 (2021): eabe3947, https://doi.org/10.1126/scitranslmed.abe3947.
- 14A. Deczkowska, A. Weiner, and I. Amit, “The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway,” Cell 6 (2020): 1207–1217, https://doi.org/10.1016/j.cell.2020.05.003.
10.1016/j.cell.2020.05.003 Google Scholar
- 15D. Feuerbach, P. Schindler, C. Barske, et al., “ADAM17 Is the Main Sheddase for the Generation of Human Triggering Receptor Expressed in Myeloid Cells (hTREM2) Ectodomain and Cleaves TREM2 After Histidine 157,” Neuroscience Letters 660 (2017): 109–114, https://doi.org/10.1016/j.neulet.2017.09.034.
- 16P. Thornton, J. Sevalle, M. J. Deery, et al., “TREM2 Shedding by Cleavage at the H157-S158 Bond Is Accelerated for the Alzheimer's Disease-Associated H157Y Variant,” EMBO Molecular Medicine 10 (2017): 1366–1378, https://doi.org/10.15252/emmm.201707673.
10.15252/emmm.201707673 Google Scholar
- 17W. Song, B. Hooli, K. Mullin, et al., “Alzheimer's Disease-Associated TREM2 Variants Exhibit Either Decreased or Increased Ligand-Dependent Activation,” Alzheimers Dement 4 (2017): 381–387, https://doi.org/10.1016/j.jalz.2016.07.004.
- 18L. Zhong, X. F. Chen, T. Wang, et al., “Soluble TREM2 Induces Inflammatory Responses and Enhances Microglial Survival,” Journal of Experimental Medicine 214, no. 3 (2017): 597–607, https://doi.org/10.1084/jem.20160844.
- 19S. H. Lee, W. J. Meilandt, L. Xie, et al., “Trem2 Restrains the Enhancement of Tau Accumulation and Neurodegeneration by β-Amyloid Pathology,” Neuron 109, no. 8 (2021): 1283–1301, https://doi.org/10.1016/j.neuron.2021.02.010.
- 20E. Morenas-Rodríguez, Y. Li, B. Nuscher, et al., “Dominantly Inherited Alzheimer Network Soluble TREM2 in CSF and Its Association With Other Biomarkers and Cognition in Autosomal-Dominant Alzheimer's Disease: A Longitudinal Observational Study,” Lancet Neurology 4 (2022): 329–341, https://doi.org/10.1016/s1474-4422(22)00027-8.
10.1016/S1474-4422(22)00027-8 Google Scholar
- 21Y. Wang, Y. Lin, L. Wang, et al., “TREM2 Ameliorates Neuroinflammatory Response and Cognitive Impairment via PI3K/AKT/FoxO3a Signaling Pathway in Alzheimer's Disease Mice,” Aging 20 (2020): 20862–20879, https://doi.org/10.18632/aging.104104.
10.18632/aging.104104 Google Scholar
- 22L. Lin, B. Ni, H. Lin, et al., “Traditional Usages, Botany, Phytochemistry, Pharmacology and Toxicology of Polygonum Multiflorum Thunb.: A Review,” Journal of Ethnopharmacology 159 (2015): 158–183, https://doi.org/10.1016/j.jep.2014.11.009.
- 23P. Sextius, R. Betts, I. Benkhalifa, et al., “Polygonum Multiflorum Radix Extract Protects Human Foreskin Melanocytes From Oxidative Stress in Vitro and Potentiates Hair Follicle Pigmentation Ex Vivo,” International Journal of Cosmetic Science 4 (2017): 419–425, https://doi.org/10.1111/ics.12391.
10.1111/ics.12391 Google Scholar
- 24P. G. Xiao, S. T. Xing, and L. W. Wang, “Immunological Aspects of Chinese Medicinal Plants as Antiageing Drugs,” Journal of Ethnopharmacology 38, no. 2-3 (1993): 167–175, https://doi.org/10.1016/0378-8741(93)90012-t.
- 25C. Shen, F. L. Sun, R. Y. Zhang, et al., “Tetrahydroxystilbene Glucoside Ameliorates Memory and Movement Functions, Protects Synapses and Inhibits α-Synuclein Aggregation in Hippocampus and Striatum in Aged Mice,” Restorative Neurology and Neuroscience 4 (2015): 531–541, https://doi.org/10.3233/rnn-150514.
10.3233/RNN-150514 Google Scholar
- 26Z. Ning, Y. Li, D. Liu, et al., “Tetrahydroxystilbene Glucoside Delayed Senile Symptoms in Old Mice via Regulation of the AMPK/SIRT1/PGC-1α Signaling Cascade,” Gerontology 64, no. 5 (2018): 457–465, https://doi.org/10.1159/000487360.
- 27R. Zhang, F. Sun, L. Zhang, X. Sun, and L. Li, “Tetrahydroxystilbene Glucoside Inhibits α-Synuclein Aggregation and Apoptosis in A53T α-Synuclein-Transfected Cells Exposed to MPP+,” Canadian Journal of Physiology and Pharmacology 6 (2017): 750–758, https://doi.org/10.1139/cjpp-2016-0209.
10.1139/cjpp-2016-0209 Google Scholar
- 28C. Jiao, F. Gao, L. Ou, et al., “Tetrahydroxy Stilbene Glycoside (TSG) Antagonizes Aβ-Induced Hippocampal Neuron Injury by Suppressing Mitochondrial Dysfunction via Nrf2-Dependent HO-1 Pathway,” Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 96 (2017): 222–228, https://doi.org/10.1016/j.biopha.2017.09.134.
- 29L. Ruan, G. Li, W. Zhao, H. Meng, Q. Zheng, and J. Wang, “Activation of Adenosine A(1) Receptor in Ischemic Stroke: Neuroprotection by Tetrahydroxy Stilbene Glycoside as an Agonist,” Antioxidants (Basel) 10 (2021): 7, https://doi.org/10.3390/antiox10071112.
10.3390/antiox10071112 Google Scholar
- 30P. Tveden-Nyborg, B. Yang, U. Simonsen, and J. Lykkesfeldt, “BCPT Perspectives on Studies Involving Natural Products, Traditional Chinese Medicine and Systems Pharmacology,” Basic & Clinical Pharmacology & Toxicology 135 (2024): 782–785.
- 31P. Tveden-Nyborg, T. K. Bergmann, N. Jessen, U. Simonsen, and J. Lykkesfeldt, “BCPT 2023 Policy for Experimental and Clinical Studies,” Basic & Clinical Pharmacology & Toxicology 133 (2023): 391–396.
- 32D. Gao, C. Chen, R. Huang, et al., “Tetrahydroxy Stilbene Glucoside Ameliorates Cognitive Impairments and Pathology in APP/PS1 Transgenic Mice,” Current Medical Science 2 (2021): 279–286, https://doi.org/10.1007/s11596-021-2344-z.
10.1007/s11596-021-2344-z Google Scholar
- 33B. B. Miao, D. Gao, J. P. Hao, et al., “Tetrahydroxy Stilbene Glucoside Alters Neurogenesis and Neuroinflammation to Ameliorate Radiation-Associated Cognitive Disability via AMPK/Tet2,” International Immunopharmacology 110 (2022): 108928, https://doi.org/10.1016/j.intimp.2022.108928.
- 34Y. Gao, J. Li, Q. Wu, et al., “Tetrahydroxy Stilbene Glycoside Ameliorates Alzheimer's Disease in APP/PS1 Mice via Glutathione Peroxidase Related Ferroptosis,” International Immunopharmacology 99 (2021): 108002, https://doi.org/10.1016/j.intimp.2021.108002.
- 35Y. Gao, K. Hu, J. Yang, et al., “Tetrahydroxy Stilbene Glycoside Regulates TGF-β/Fractalkine/CX3CR1 Based on Network Pharmacology in APP/PS1 Mouse Model,” Neuropeptides 90 (2021): 102197, https://doi.org/10.1016/j.npep.2021.102197.
- 36H. S. Kwon and S. H. Koh, “Neuroinflammation in Neurodegenerative Disorders: The Roles of Microglia and Astrocytes,” Translational Neurodegeneration 1 (2020): 42, https://doi.org/10.1186/s40035-020-00221-2.
10.1186/s40035-020-00221-2 Google Scholar
- 37L. Zhong, Y. Xu, R. Zhuo, et al., “Soluble TREM2 Ameliorates Pathological Phenotypes by Modulating Microglial Functions in an Alzheimer's Disease Model,” Nature Communications 1 (2019): 1365, https://doi.org/10.1038/s41467-019-09118-9.
10.1038/s41467-019-09118-9 Google Scholar
- 38Y. Shi and D. M. Holtzman, “Interplay Between Innate Immunity and Alzheimer Disease: APOE and TREM2 in the Spotlight,” Nature Reviews. Immunology 12 (2018): 759–772, https://doi.org/10.1038/s41577-018-0051-1.
10.1038/s41577-018-0051-1 Google Scholar
- 39J. Hou, Y. Chen, G. Grajales-Reyes, and M. Colonna, “TREM2 Dependent and Independent Functions of Microglia in Alzheimer's Disease,” Molecular Neurodegeneration 17, no. 1 (2022): 84, https://doi.org/10.1186/s13024-022-00588-y.
- 40D. R. Hou, Y. Wang, L. Xue, et al., “Effect of Polygonum Multiflorum on the Fluidity of the Mitochondria Membrane and Activity of COX in the Hippocampus of Rats With Abeta 1-40- Induced Alzheimer's Disease,” Zhong Nan Da Xue Xue Bao. Yi Xue Ban 11 (2008): 987–992.
- 41S. Xu, J. Liu, J. Shi, Z. Wang, and L. Ji, “2,3,4′,5-Tetrahydroxystilbene-2-O-β-D-Glucoside Exacerbates Acetaminophen-Induced Hepatotoxicity by Inducing Hepatic Expression of CYP2E1, CYP3A4 and CYP1A2,” Scientific Reports 1 (2017): 16511, https://doi.org/10.1038/s41598-017-16688-5.
10.1038/s41598-017-16688-5 Google Scholar
- 42C. Büchter, L. Zhao, S. Havermann, et al., “TSG (2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-Glucoside) From the Chinese Herb Polygonum Multiflorum Increases Life Span and Stress Resistance of Caenorhabditis Elegans,” Oxidative Medicine and Cellular Longevity 2015 (2015): 124357, https://doi.org/10.1155/2015/124357.
- 43T. Wang, J. Gu, P. F. Wu, et al., “Protection by Tetrahydroxystilbene Glucoside Against Cerebral Ischemia: Involvement of JNK, SIRT1, and NF-kappaB Pathways and Inhibition of Intracellular ROS/RNS Generation,” Free Radical Biology & Medicine 3 (2009): 229–240, https://doi.org/10.1016/j.freeradbiomed.2009.02.027.
- 44Z. Jiang, W. Wang, and C. Guo, “Tetrahydroxy Stilbene Glucoside Ameliorates H2O2-Induced Human Brain Microvascular Endothelial Cell Dysfunction in Vitro by Inhibiting Oxidative Stress and Inflammatory Responses,” Molecular Medicine Reports 4 (2017): 5219–5224, https://doi.org/10.3892/mmr.2017.7225.
10.3892/mmr.2017.7225 Google Scholar
- 45Y. Gao, J. Li, J. Li, et al., “Tetrahydroxy Stilbene Glycoside Alleviated Inflammatory Damage by Mitophagy via AMPK Related PINK1/Parkin Signaling Pathway,” Biochemical Pharmacology 177 (2020): 113997, https://doi.org/10.1016/j.bcp.2020.113997.
- 46Y. Zou and M. Kong, “Tetrahydroxy Stilbene Glucoside Alleviates Palmitic Acid-Induced Inflammation and Apoptosis in Cardiomyocytes by Regulating miR-129-3p/Smad3 Signaling,” Cellular & Molecular Biology Letters 24 (2019): 5, https://doi.org/10.1186/s11658-018-0125-x.
- 47L. Zhang, S. Yu, R. Zhang, Y. Xing, Y. Li, and L. Li, “Tetrahydroxystilbene Glucoside Antagonizes Age-Related α- Synuclein Overexpression in the Hippocampus of APP Transgenic Mouse Model of Alzheimer's Disease,” Restorative Neurology and Neuroscience 1 (2013): 41–52, https://doi.org/10.3233/rnn-120260.
10.3233/RNN-120260 Google Scholar
- 48Z. Cai, M. D. Hussain, and L. J. Yan, “Microglia, Neuroinflammation, and Beta-Amyloid Protein in Alzheimer's Disease,” International Journal of Neuroscience 5 (2014): 307–321, https://doi.org/10.3109/00207454.2013.833510.
10.3109/00207454.2013.833510 Google Scholar
- 49M. Chen, M. L. Vial, J. Tello Velasquez, J. A. K. Ekberg, R. A. Davis, and J. A. St John, “The Serrulatane Diterpenoid Natural Products RAD288 and RAD289 Stimulate Properties of Olfactory Ensheathing Cells Useful for Neural Repair Therapies,” Scientific Reports 1 (2018): 10240, https://doi.org/10.1038/s41598-018-28551-2.
10.1038/s41598-018-28551-2 Google Scholar
- 50H. Sarlus and M. T. Heneka, “Microglia in Alzheimer's Disease,” Journal of Clinical Investigation 9 (2017): 3240–3249, https://doi.org/10.1172/jci90606.
- 51Y. Gao, “Inflammation and Gut Microbiota in the Alcoholic Liver Disease,” Food & Medicine Homology 1 (2024): 9420020, https://doi.org/10.26599/FMH.2024.9420020.
10.26599/FMH.2024.9420020 Google Scholar
- 52D. Y. Wang, B. Yan, A. Wang, et al., “Tu-Xian Decoction Ameliorates Diabetic Cognitive Impairment by Inhibiting DAPK-1,” Chinese Journal of Natural Medicines 21, no. 12 (2023): 950–960, https://doi.org/10.1016/S1875-5364(23)60428-5.
- 53Y. Huang, H. L. Yang, B. Y. Yang, et al., “Ginsenoside-Rg1 Combined With a Conditioned Medium From Induced Neuron-Like hUCMSCs Alleviated the Apoptosis in a Cell Model of ALS Through Regulating the NF-κB/Bcl-2 Pathway,” Chinese Journal of Natural Medicines 21, no. 7 (2023): 540–550, https://doi.org/10.1016/S1875-5364(23)60445-5.
- 54A. McQuade, Y. J. Kang, J. Hasselmann, et al., “Gene Expression and Functional Deficits Underlie TREM2-Knockout Microglia Responses in Human Models of Alzheimer's Disease,” Nature Communications 1 (2020): 5370, https://doi.org/10.1038/s41467-020-19227-5.
10.1038/s41467-020-19227-5 Google Scholar
- 55T. K. Ulland and M. Colonna, “TREM2—A key Player in Microglial Biology and Alzheimer Disease,” Nature Reviews. Neurology 11 (2018): 667–675, https://doi.org/10.1038/s41582-018-0072-1.
10.1038/s41582-018-0072-1 Google Scholar
- 56Y. Zhou, W. M. Song, P. S. Andhey, et al., “Human and Mouse Single-Nucleus Transcriptomics Reveal TREM2-Dependent and TREM2-Independent Cellular Responses in Alzheimer's Disease,” Nature Medicine 1 (2020): 131–142, https://doi.org/10.1038/s41591-019-0695-9.
10.1038/s41591-019-0695-9 Google Scholar
- 57Y. S. Fan, Q. Li, N. Hamdan, et al., “Tetrahydroxystilbene Glucoside Regulates Proliferation, Differentiation, and OPG/RANKL/M-CSF Expression in MC3T3-E1 Cells via the PI3K/Akt Pathway,” Molecules 23, no. 9 (2018): 2306, https://doi.org/10.3390/molecules23092306.
- 58R. Y. Li, Q. Qin, H. C. Yang, et al., “TREM2 in the Pathogenesis of AD: A Lipid Metabolism Regulator and Potential Metabolic Therapeutic Target,” Molecular Neurodegeneration 17, no. 1 (2022): 40, https://doi.org/10.1186/s13024-022-00542-y.
- 59Y. Wang, T. K. Ulland, J. D. Ulrich, et al., “TREM2-Mediated Early Microglial Response Limits Diffusion and Toxicity of Amyloid Plaques,” Journal of Experimental Medicine 213, no. 5 (2016): 667–675, https://doi.org/10.1084/jem.20151948.
- 60X. S. Ye, W. J. Tian, G. H. Wang, et al., “The Food and Medicine Homologous Chinese Medicine From Leguminosae Species: A Comprehensive Review on Bioactive Constituents With Neuroprotective Effects on Nervous System,” Food & Medicine Homology 2 (2025): 9420033, https://doi.org/10.26599/FMH.2025.9420033.
10.26599/FMH.2025.9420033 Google Scholar
- 61G. Luo, X. Wang, Y. Cui, Y. Cao, Z. Zhao, and J. Zhang, “Metabolic Reprogramming Mediates Hippocampal Microglial M1 Polarization in Response to Surgical Trauma Causing Perioperative Neurocognitive Disorders,” Journal of Neuroinflammation 1 (2021): 267, https://doi.org/10.1186/s12974-021-02318-5.
10.1186/s12974-021-02318-5 Google Scholar
- 62S. C. Huang, B. Everts, Y. Ivanova, et al., “Cell-Intrinsic Lysosomal Lipolysis Is Essential for Alternative Activation of Macrophages,” Nature Immunology 9 (2014): 846–855, https://doi.org/10.1038/ni.2956.
10.1038/ni.2956 Google Scholar
