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中华老年病研究电子杂志

中华老年病研究电子杂志 ›› 2024, Vol. 11 ›› Issue (01) : 51 -56. doi: 10.3877/cma.j.issn.2095-8757.2024.01.010

综述

髓系细胞触发受体2在β淀粉样蛋白病理致阿尔茨海默病中的作用机制
陆静1, 钟为慧2, 赵杰3, 曾玲晖3,†()   
  1. 1. 310014　湖州，浙江工业大学药学院；310015　杭州，浙大城市学院医学院
    2. 310014　湖州，浙江工业大学药学院
    3. 310015　杭州，浙大城市学院医学院
  • 收稿日期:2023-10-26 出版日期:2024-02-28
  • 通信作者: 曾玲晖
  • 基金资助:
    浙江省自然科学基金资助项目(LTGD23C050001)

The mechanism of triggering receptor expressed on myeloid cells-2 in Alzheimer’s disease due to amyloid β-protein pathology

Jing Lu1, Weihui Zhong2, Jie Zhao3, Linghui Zeng3,†()   

  1. 1. College of Pharmaceutical Sciences, Zhejiang University of Technology, Huzhou 310014, China; School of Medicine, Hangzhou City University, Hangzhou 310015, China
    2. College of Pharmaceutical Sciences, Zhejiang University of Technology, Huzhou 310014, China
    3. School of Medicine, Hangzhou City University, Hangzhou 310015, China
  • Received:2023-10-26 Published:2024-02-28
  • Corresponding author: Linghui Zeng
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陆静, 钟为慧, 赵杰, 曾玲晖. 髓系细胞触发受体2在β淀粉样蛋白病理致阿尔茨海默病中的作用机制[J]. 中华老年病研究电子杂志, 2024, 11(01): 51-56.

Jing Lu, Weihui Zhong, Jie Zhao, Linghui Zeng. The mechanism of triggering receptor expressed on myeloid cells-2 in Alzheimer’s disease due to amyloid β-protein pathology[J]. Chinese Journal of Geriatrics Research(Electronic Edition), 2024, 11(01): 51-56.

髓系细胞触发受体2（TREM2）是近年来发现的阿尔茨海默病（AD）的重要风险基因，在AD的发生和进展中发挥着重要作用。本文从AD中淀粉样蛋白及其与TREM2的相互作用、TREM2过表达增强与β淀粉样蛋白（Aβ）相互作用来减弱Aβ病理、Aβ磷酸化修饰增强与TREM2相互作用调节小胶质细胞摄取和针对可溶性TREM2的靶向治疗可能通过调节小胶质细胞活化清除Aβ几个方面进行综述，为进一步了解TREM2在Aβ病理致AD中的作用机制和AD的治疗提供参考。

关键词: 阿尔茨海默病, 髓系细胞触发受体2, β淀粉样蛋白, 小胶质细胞, 相互作用

The triggering receptor expressed on myeloid cells-2 (TREM2) has been identified as a significant risk factor for Alzheimer's disease (AD) in recent years. It plays an important role in the development and progression of AD. In this paper, we review amyloid β-protein (Aβ) and its interaction with TREM2 in AD, TREM2 overexpression enhancing interaction with Aβ to attenuate Aβ pathology, Aβ phosphorylation modification enhancing interaction between Aβ and TREM2 to regulate microglial uptake, and targeted therapies against sTREM2 to potentially clear Aβ by regulating microglial activation, so as to further understand the mechanism of TREM2 in Aβ pathogenesis, and to provide reference for the treatment of AD.

Key words: Alzheimer's disease, Triggering receptor expressed on myeloid cells-2, Amyloid β-protein, Microglia, Interaction
图1 TREM2介导的小胶质细胞Aβ清除过程注：Resting microglia指静息态小胶质细胞；LPS指脂多糖；ApoE指载脂蛋白E；Aβ指β淀粉样蛋白；TREM2指髓系细胞触发受体2；sTREM2指可溶性TREM2；DAP指DNAX活化蛋白；Classical activation指经典激活；Alternative activation指替代激活；Acquired deactivation指获得性失活；TNF-α指肿瘤坏死因子-α；INF-γ指γ-干扰素；IL指白细胞介素；TGF-β指转化生长因子；Syk指酪氨酸激酶；PI3K指磷脂酰肌醇激酶；mTOR指哺乳动物雷帕霉素靶蛋白；Akt指蛋白激酶B；GSK3β指丝氨酸/苏氨酸激酶
图2 Aβ的产生和修饰途径注：P3指APP非淀粉样蛋白细胞外片段；C83指含有83个氨基酸的羧基端片段；C99指含有99个氨基酸的羧基端片段；Aβ指β淀粉样蛋白；APP指淀粉样前体蛋白；sAPP指可溶性APP；AICD指APP胞内结构域；OAβ指Aβ寡聚体；Aβ fibrils指Aβ纤维；Aβ plaques指Aβ斑块；PTM指翻译后修饰；Phosphorylated Aβ指磷酸化Aβ；Nitrated Aβ指硝化Aβ；Pyroglutamated Aβ指焦谷氨酸Aβ；Truncated Aβ指截短的Aβ
表1 β淀粉样蛋白翻译后修饰对聚集和毒性的影响
修饰位点 修饰类型 聚集特性 毒性影响 参考文献
S8、S26 磷酸化 pSer8促进了Aβ的原纤维化，而pSer26则稳定了寡聚体的组装 Aβ磷酸化修饰促进了TREM2与Aβ寡聚体之间的相互作用，并增加了神经毒性 [27]
E3、E11 焦谷氨酸化 更容易形成β折叠结构，增强了在低聚物和原纤维中的聚集能力，相较于全长的Aβ，具有更高的寡聚化和聚集倾向 毒性特征与Aβ1-42相似，具有广泛的神经毒性 [24，25，26，27，28]
Met35 氧化 抑制Aβ原纤维和单体原纤维的形成，减少Aβ1-40低聚物的形成 无神经毒性 [29]
Y10 硝化 在体外形成高分子量聚集物的倾向性增加 抑制神经毒性 [30]
K16、K28 乙酰化 减缓了Aβ42纤维化速度，但不影响纤维形态 增加活性氧，增加细胞毒性 [31]
氨基端或R/K的侧链上 糖基化 减慢成熟纤维的形成，但不改变聚集体的形态 毒性增加 [32]
Asn27 脱酰胺 Aβ1-40阻碍原纤维化并诱导形成反平行β折叠的聚集体；Aβ1-42部分形成了原纤维，并参与了平行的β折叠结构 毒性降低 [33]
Arg5 瓜氨酸化 Aβ1-40瓜氨酸化不影响纤维化速度，与Aβ1-40原纤维不同的β折叠结构；在水性介质的溶解性增加，原纤维形成速度比Aβ42慢 毒性降低 [33，34]
[1]
Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer's disease[J]. Lancet, 2021, 397(10284):1577-1590.
[2]
Ullah R, Park TJ, Huang X, et al. Abnormal amyloid beta metabolism in systemic abnormalities and Alzheimer's pathology: Insights and therapeutic approaches from periphery[J]. Ageing Res Rev, 2021, 71:101451-101274.
[3]
Atri A. Current and future treatments in Alzheimer's disease[J]. Semin Neurol, 2019, 39(2):227-240.
[4]
Merlo D, Cuchillo-Ibanez I, Parlato R, et al. DNA damage, neurodegeneration, and synaptic plasticity[J]. Neural Plast, 2016, 2016:1206840-1206842.
[5]
Hardy JA, Higgins GA. Alzheimer's disease: The amyloid cascade hypothesis[J]. Science, 1992, 256(5054):184-185.
[6]
Zhao Y, Wu X, Li X, et al. TREM2 is a receptor for beta-amyloid that mediates microglial function[J]. Neuron, 2018, 97(5):1023-1031.
[7]
Edwards FA. A unifying hypothesis for Alzheimer's disease: From plaques to neurodegeneration[J]. Trends Neurosci, 2019, 42(5):310-322.
[8]
Zheng H, Jia L, Liu CC, et al. TREM2 promotes microglial survival by activating Wnt/beta-catenin pathway[J]. J Neurosci, 2017, 37(7):1772-1784.
[9]
Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer's disease[J]. N Engl J Med, 2013, 368(2):117-127.
[10]
Zhao P, Xu Y, Fan X, et al. Discovery and engineering of an anti-TREM2 antibody to promote amyloid plaque clearance by microglia in 5XFAD mice[J]. MAbs, 2022, 14(1):2107971.
[11]
Zhao P, Xu Y, Jiang L, et al. A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer's disease[J]. Sci Transl Med, 2022, 14(661):eabq0095.
[12]
Zhao N, Qiao W, Li F, et al. Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia[J]. J Exp Med, 2022, 219(12):479-506.
[13]
Ma C, Hong F, YANG S. Amyloidosis in Alzheimer's disease: Pathogeny, etiology, and related therapeutic directions[J]. Molecules, 2022, 27(4): 1210-1221.
[14]
Chen GF, Xu TH, Yan Y, et al. Amyloid beta: Structure, biology and structure-based therapeutic development[J]. Acta Pharmacol Sin, 2017, 38(9):1205-1235.
[15]
Zhang YL, Wang J, Zhang ZN, et al. The relationship between amyloid-beta and brain capillary endothelial cells in Alzheimer's disease[J]. Neural Regener Res, 2022, 17(11):2355-2363.
[16]
Canevari L, Abramov AY, Duchen MR. Toxicity of amyloid beta peptide: Tales of calcium, mitochondria, and oxidative stress[J]. Neurochem Res, 2004, 29(3):637-650.
[17]
Popescu AS, Butler CA, Allendorf DH, et al. Alzheimer's disease-associated R47H TREM2 increases, but wild-type TREM2 decreases, microglial phagocytosis of synaptosomes and neuronal loss[J]. Glia, 2023, 71(4):974-990.
[18]
Wang Y, Ulland TK, Ulrich JD, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques[J]. J Exp Med, 2016, 213(5):667-675.
[19]
Zhong L, Wang Z, Wang D, et al. Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2)[J]. Mol Neurodegener, 2018, 13(1):15-26.
[20]
Lessard CB, Malnik SL, Zhou Y, et al. High-affinity interactions and signal transduction between Aβ oligomers and TREM2[J/OL]. EMBO Mol Med, 2018, 10(11):E9027.
[21]
Ruganzu JB, Zheng Q, Wu X, et al. TREM2 overexpression rescues cognitive deficits in APP/PS1 transgenic mice by reducing neuroinflammation via the JAK/STAT/SOCS signaling pathway[J]. Exp Neurol, 2021, 336(3):3506-3527.
[22]
Lessard CB, Malnik SL, Zhou Y, et al. High-affinity interactions and signal transduction between Abeta oligomers and TREM2[J]. EMBO Mol. Med, 2018, 10(11):9027-9039.
[23]
Shi Q, Chang C, Saliba A, et al. Microglial mTOR activation upregulates Trem2 and enhances beta-amyloid plaque clearance in the 5XFAD Alzheimer's disease model[J]. J Neurosci, 2022, 42(27):5294-5313.
[24]
Kummer MP, Heneka MT. Truncated and modified amyloid-beta species[J]. Alzheimers Res Ther, 2014, 6(3):28-36.
[25]
李高，李艳梅.截短与修饰的β-淀粉样蛋白与阿尔茨海默病[J].化学进展，2020，32（1）：14-22.
[26]
Joshi P, Riffel F, Kumar S, et al. TREM2 modulates differential deposition of modified and non-modified Abeta species in extracellular plaques and intraneuronal deposits[J]. Acta Neuropathol Commun, 2021, 9(1):168-189.
[27]
Joshi P, Riffel F, Satoh K, et al. Differential interaction with TREM2 modulates microglial uptake of modified Abeta species[J]. Glia, 2021, 69(12):2917-2932.
[28]
Gunn AP, Masters CL, Cherny RA. Pyroglutamate-Abeta: Role in the natural history of Alzheimer's disease[J]. Int J Biochem Cell Biol, 2010, 42(12): 1915-1918.
[29]
Palmblad M, Westlind-danielsson A, Bergquist J. Oxidation of methionine 35 attenuates formation of amyloid beta -peptide 1-40 oligomers[J]. J Biol Chem, 2002, 277(22):19506-19510.
[30]
Kummer MP, Hermes M, Delekarte A, et al. Nitration of tyrosine 10 critically enhances amyloid beta aggregation and plaque formation[J]. Neuron, 2011, 71(5):833-844.
[31]
Adhikari R, Yang M, Saikia N, et al. Acetylation of abeta42 at lysine 16 disrupts amyloid formation[J]. ACS Chem Neurosci, 2020, 11(8):1178-1191.
[32]
Emendato A, Milordini G, Zacco E, et al. Glycation affects fibril formation of Abeta peptides[J]. J Biol Chem, 2018, 293(34):13100-13111.
[33]
Osaki D, Hiramatsu H. Citrullination and deamidation affect aggregation properties of amyloid beta-proteins[J]. Amyloid, 2016, 23(4):234-241.
[34]
Mukherjee S, Perez KA, Dubois C, et al. Citrullination of amyloid-beta peptides in Alzheimer's disease[J]. ACS Chem Neurosci, 2021, 12(19):3719-3732.
[35]
La Rosa F, Agostini S, Piancone F, et al. TREM2 expression and amyloid-beta phagocytosis in Alzheimer's disease[J]. Int J Mol Sci, 2023, 24(10):8626-8640.
[36]
Schlepckow K, Monroe KM, Kleinberger G, et al. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region[J/OL]. EMBO Mol Med, 2020, 12(4):e11227.
[37]
Jain N, Lewis CA, Ulrich JD, et al. Chronic TREM2 activation exacerbates Abeta-associated tau seeding and spreading[J/OL]. J Exp Med, 2023, 220(1):e20220654.
[38]
Wang S, Mustafa M, Yuede CM, et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model[J/OL]. J Exp Med, 2020, 217(9):e20200785.
[39]
Van Lengerich B, Zhan L, Xia D, et al. A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models[J]. Nat Neurosci, 2023, 26(3):416-429.
[40]
Feuerbach D, Schindler P, Barske C, 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[J]. Neurosci Lett, 2017, 660:109-114.
[41]
Dhandapani R, Neri M, Bernhard M, et al. Sustained Trem2 stabilization accelerates microglia heterogeneity and Abeta pathology in a mouse model of Alzheimer's disease[J]. Cell Rep, 2022, 39(9):110883.
[42]
Morenas-Rodriguez E, Li Y, Nuscher B, et al. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: A longitudinal observational study[J]. Lancet Neurol, 2022, 21(4):329-341.
[43]
Weber GE, Khrestian M, Tuason ED, et al. Peripheral sTREM2-related inflammatory activity alterations in early-stage Alzheimer's disease[J]. J Immunol, 2022, 208(10):2283-2299.
[44]
Filipello F, Goldsbury C, You SF, et al. Soluble TREM2: Innocent bystander or active player in neurological diseases[J]? Neurobiol Dis, 2022, 165:105630.
[45]
Brendel M, Kleinberger G, Probst F, et al. Increase of TREM2 during aging of an Alzheimer's disease mouse model is paralleled by microglial activation and amyloidosis[J]. Front Aging Neurosci, 2017, 9:8-20.
[46]
Kleinberger G, Brendel M, Mracsko E, et al. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism[J]. EMBO J, 2017, 36(13):1837-1853.
[47]
Franzmeier N, Suarez-Calvet M, Frontzkowski L, et al. Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration[J]. Mol Neurodegener, 2020, 15(1):57-66.
[48]
Sheng X, Yao Y, Huang R, et al. Identification of the minimal active soluble TREM2 sequence for modulating microglial phenotypes and amyloid pathology[J]. J Neuroinflammation, 2021, 18(1):286-297.
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