The Role of TREM2 Receptor in Alzheimer’s Disease

DAI Yuting; SHI Jingming

doi:10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.20240419.006

您当前的位置：

首页 >

文章列表页 >

The Role of TREM2 Receptor in Alzheimer’s Disease

Review | 更新时间：2024-06-05

- The Role of TREM2 Receptor in Alzheimer’s Disease
- Journal of Sun Yat-sen University(Medical Sciences) Vol. 45, Issue 3, Pages: 344-353(2024)
- 作者机构：
  
  西藏民族大学医学院高原环境脑神经损伤与修复研究实验室，陕西咸阳，712082
- 作者简介：
  
  SHI Jingming； E-mail： jmshi@xzmu.edu.cn
- 基金信息：
- DOI：10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.20240419.006
  CLC： R518.4
- Published：20 May 2024，
  
  Received：27 November 2023，
  
  Accepted：08 April 2024
扫描看全文
代玉婷,石镜明.髓系细胞触发受体2在阿尔茨海默病中的作用[J].中山大学学报（医学科学版）,2024,45(03):344-353.

DAI Yuting,SHI Jingming.The Role of TREM2 Receptor in Alzheimer’s Disease[J].Journal of Sun Yat-sen University(Medical Sciences),2024,45(03):344-353.
代玉婷,石镜明.髓系细胞触发受体2在阿尔茨海默病中的作用[J].中山大学学报（医学科学版）,2024,45(03):344-353. DOI： 10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.20240419.006.

DAI Yuting,SHI Jingming.The Role of TREM2 Receptor in Alzheimer’s Disease[J].Journal of Sun Yat-sen University(Medical Sciences),2024,45(03):344-353. DOI： 10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.20240419.006.

摘要

阿尔茨海默病（AD）是老年性痴呆症中最常见的形式，其发病机制仍不清楚，但β淀粉样蛋白（Aβ）被认为是引起AD发病的重要原因，然而其引发AD的病理机制同样存在多种争议。最近研究显示，髓系细胞触发受体（TREM2）在AD病理进程中扮演重要角色，其不仅可以作为Aβ内化的重要受体，还可能成为生物学诊断标志物和治疗靶点，阐明TREM2的结构和功能，将为AD的防治提供重要的思路。本文将从TREM2的结构、TREM2对小胶质细胞功能的影响、TREM2在AD中的病理学作用以及靶向TREM2治疗AD的现状进行系统性综述，这些总结将为AD的基础研究提供具有价值的参考。

Abstract

Alzheimer's disease （AD） is the most common form of senile dementia， and its pathogenesis is still unclear. While β-amyloid （Aβ） is considered an important cause of AD， the pathological mechanism of Aβ inducing AD is subject to various controversies. Recent studies have shown that the myeloid cell trigger receptor （TREM2） plays an important role in the pathological process of AD， and it can not only serve as an important receptor for the internalization of Aβ but also become a biological diagnostic biomarker and therapeutic target. Hence， elucidating the structure and function of TREM2 will provide important ideas for the prevention and treatment of AD. This article will provide a systematic review of the structure of TREM2， its impact on microglial cell function， its pathological role in AD， and the current status of targeted TREM2 therapy for AD. These summaries will provide valuable references for basic research on AD.

关键词

阿尔茨海默病髓系细胞触发受体小胶质细胞β淀粉样蛋白细胞受体

Keywords

Alzheimer's diseaseTREM2microgliaβ-amyloidcell receptors

references

Tiwari S， Atluri V， Kaushik A， et al. Alzheimer's disease： pathogenesis， diagnostics， and therapeutics ［J］. Int J Nanomedicine， 2019， 14：5541-5554.

Self WK， Holtzman DM. Emerging diagnostics and therapeutics for Alzheimer disease ［J］. Nat Med， 2023， 29（9）：2187-2199.

Monteiro AR， Barbosa DJ， Remião F， et al. Alzheimer's disease： Insights and new prospects in disease pathophysiology， biomarkers and disease-modifying drugs ［J］. Biochem Pharmacol， 2023， 211：115522.

王曌慧，刘潇，周玥，等. 髓系细胞触发受体2在高糖处理的小胶质细胞中的表达及作用［J］. 基础医学与临床， 2024， 44（2）：167-173.

Wang ZH， Liu X， Zhou Y， et al. Expression and role of myeloid cell trigger receptor 2 in high glucose treated microglia ［J］ Basic Clin Med， 2024， 44 （2）： 167-173.

国佳莹，石京山.小胶质细胞表型和功能的多样性与阿尔茨海默症［J］. 遵义医科大学学报，2020，43（3）：405-411.

Guo JY，Shi JS. Role of diversity of phenotype and function of microglia on the pathogenesis of Alzheimer's disease［J］. J Zunyi Med Univ，2020，43（3）：405-411.

Ayyubova G. TREM2 signalling as a multifaceted player in brain homoeostasis and a potential target for Alzheimer's disease treatment ［J］. Eur J Neurosci， 2023， 57（4）：718-733.

Wang L， Nykänen NP， Western D， et al. Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease［J］. Mol Neurodegener， 2024， 19（1）： 1.

Moonen S， Koper MJ， Van Schoor E， et al. Pyroptosis in Alzheimer’s disease： cell type-specific activation in microglia， astrocytes and neurons［J］. Acta Neuropathol， 2023， 145（2）： 175-195.

Taddei RN， Perbet R， de Gerando AM， et al. Tau Oligomer–Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease［J］. JAMA neurology， 2023， 80（11）： 1209-1221.

师利敏，徐平. 髓系细胞触发受体2在认知功能障碍中相关机制的研究进展［J］. 中山大学学报（医学科学版），2024，45（1）：7-12.

Shi LM， Xu P. Research progress on the mechanism of triggering receptor 2 in myeloid cells in cognitive dysfunction ［J］. J Sun Yat-sen Univ（Med Sci）， 2024，45 （1）： 7-12.

Peng X， Guo H， Zhang X， et al. TREM2 inhibits tau hyperphosphorylation and neuronal apoptosis via the PI3K/Akt/GSK-3β signaling pathway in vivo and in vitro［J］. Mol Neurobiol， 2023， 60（5）： 2470-2485.

Merighi S， Nigro M， Travagli A， et al. Microglia and Alzheimer’s disease［J］. Int J Mol Sci， 2022， 23（21）： 12990.

Deczkowska A， Weiner A， Amit I. The physiology， pathology， and potential therapeutic applications of the TREM2 signaling pathway［J］. Cell， 2020， 181（6）： 1207-1217.

Yeh FL， Hansen DV， Sheng M. TREM2， microglia， and neurodegenerative diseases［J］. Trends Mol Med， 2017， 23（6）： 512-533.

Kober DL， Brett TJ. TREM2-ligand interactions in health and disease［J］. J Mol Biol， 2017， 429（11）： 1607-1629.

Zhong L， Xu Y， Zhuo R， et al. Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model［J］. Nat Commun， 2019， 10（1）： 1365.

Belsare KD， Wu H， Mondal D， et al. Soluble TREM2 inhibits secondary nucleation of Aβ fibrillization and enhances cellular uptake of fibrillar Aβ［J］. Proc Natl Acad Sci U S A， 2022， 119（5）： e2114486119.

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.

Brown GC， George-Hyslop S. Does soluble TREM2 protect against Alzheimer's disease？［J］. Front Aging Neurosci， 2022， 13： 834697.

Ferrara SJ， Chaudhary P， DeBell MJ， et al. TREM2 is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor［J］. Cell Chem Biol， 2022， 29（2）： 239-248. e4.

Li RY， Qin Q， Yang HC， et al. TREM2 in the pathogenesis of AD： a lipid metabolism regulator and potential metabolic therapeutic target［J］. Mol Neurodegener， 2022， 17（1）： 40.

Wolfe CM， Fitz NF， Nam KN， et al. The role of APOE and TREM2 in Alzheimer' s disease—current understanding and perspectives［J］. Int J Mol Sci， 2018， 20（1）： 81.

Mecca C， Giambanco I， Donato R， et al. Microglia and aging： the role of the TREM2–DAP12 and CX3CL1-CX3CR1 axes［J］. Int J Mol Sci， 2018， 19（1）： 318.

Gratuze M， Leyns CEG， Holtzman DM. New insights into the role of TREM2 in Alzheimer’s disease［J］. Mol Neurodegener， 2018， 13（1）： 66.

Qiao X， Wang H， He Y， et al. Grape Seed Proanthocyanidin Ameliorates LPS-induced Acute Lung Injury By Modulating M2a Macrophage Polarization Via the TREM2/PI3K/Akt Pathway［J］. Inflammation， 2023， 46（6）： 2147-2164.

Chen S， Peng J， Sherchan P， et al. TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice［J］. J Neuroinflammation， 2020， 17： 1-16.

He GL， Luo Z， Shen TT， et al. TREM2 regulates heat acclimation-induced microglial M2 polarization involving the PI3K-Akt pathway following EMF exposure［J］. Front Cell Neurosci， 2020， 13： 591.

Bai M， Yin HP， Zhao J， et al. Roles of TREM2 in degeneration of human nucleus pulposus cells via NF‐κB p65［J］. J Cell Biochem， 2018， 119（11）： 8784-8796.

Wang M， Pan W， Xu Y， et al. Microglia-mediated neuroinflammation： a potential target for the treatment of cardiovascular diseases［J］. J Inflamm Res， 2022： 3083-3094.

Gui J， Liu J， Wang L， et al. TREM2 mitigates NLRP3-mediated neuroinflammation through the NF-κB and PI3k/Akt signaling pathways in juvenile rats exposed to ambient particulate matter［J］. Environ Sci Pollut Res Int， 2023， 30（57）： 119863-119878.

Liu S， Cao X， Wu Z， et al. TREM2 improves neurological dysfunction and attenuates neuroinflammation， TLR signaling and neuronal apoptosis in the acute phase of intracerebral hemorrhage［J］. Front Aging Neurosci， 2022， 14： 967825.

De Sousa JAC， Azul FVCS， de Araújo AB， et al. Epiisopiloturine， an alkaloid from pilocarpus microphyllus， attenuates LPS-induced neuroinflammation by interfering in the TLR4/NF-κB-MAPK signaling pathway in microglial cells ［J］. Oxid Med Cell Longev， 2023， 2023：4752502.

Ruganzu JB， Peng X， He Y， et al. Downregulation of TREM2 expression exacerbates neuroinflammatory responses through TLR4-mediated MAPK signaling pathway in a transgenic mouse model of Alzheimer’s disease［J］. Mol Immunol， 2022， 142： 22-36.

Zhang J， Liu Y， Zheng Y， et al. TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus［J］. J Neuroinflammation， 2020， 17： 1-16.

Zhou SL， Tan CC， Hou XH， et al. TREM2 variants and neurodegenerative diseases： a systematic review and meta-analysis［J］. J Alzheimers Dis， 2019， 68（3）： 1171-1184.

Guerreiro R， Wojtas A， Bras J， et al. TREM2 variants in Alzheimer's disease［J］. N Engl J Med， 2013， 368（2）： 117-127.

Rikos D， Siokas V， Mentis AFA， et al. TREM2 R47H variant and risk for Alzheimer’s disease： assessment in a Greek population and updated meta-analysis［J］. Int J Neurosci， 2022： 1-9.

Cosker K， Mallach A， Limaye J， et al. Microglia signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome［J］. Sci Rep， 2021， 11（1）： 13316.

Huang W， Huang J， Huang N， et al. The role of TREM2 in Alzheimer's disease： from the perspective of Tau ［J］. Front Cell Dev Biol， 2023， 11：1280257.

Jin SC， Carrasquillo MM， Benitez BA， et al. TREM2 is associated with increased risk for Alzheimer's disease in African Americans ［J］. Mol Neurodegener， 2015， 10： 1-7.

Jiang T， Tan L， Chen Q， et al. A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese［J］. Neurobiol Aging， 2016， 42： 217. e1-217. e3.

Song W， Hooli B， Mullin K， et al. Alzheimer's disease‐associated TREM2 variants exhibit either decreased or increased ligand‐dependent activation［J］. Alzheimers Dement， 2017， 13（4）： 381-387.

Thornton P， Sevalle J， Deery MJ， et al. TREM 2 shedding by cleavage at the H157‐S158 bond is accelerated for the Alzheimer's disease‐associated H157Y variant［J］. EMBO Mol Med， 2017， 9（10）： 1366-1378.

Qiao W， Chen Y， Zhong J， et al. Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology［J］. Mol Neurodegener， 2023， 18（1）： 8.

Olufunmilayo EO， Holsinger RMD. Variant TREM2 signaling in Alzheimer's disease［J］. J Mol Biol， 2022， 434（7）： 167470.

Dean HB， Roberson ED， Song Y. Neurodegenerative disease–associated variants in TREM2 destabilize the apical ligand-binding region of the immunoglobulin domain［J］. Front Neurol， 2019， 10： 485726.

Lessard CB， Malnik SL， Zhou Y， et al. High‐affinity interactions and signal transduction between Aβ oligomers and TREM 2［J］. EMBO Mol Med， 2018， 10（11）： e9027.

Yeh FL， Wang Y， Tom I， et al. TREM2 binds to apolipoproteins， including APOE and CLU/APOJ， and thereby facilitates uptake of amyloid-beta by microglia［J］. Neuron， 2016， 91（2）： 328-340.

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.

Wang Y， Cella M， Mallinson K， et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model［J］. Cell， 2015， 160（6）： 1061-1071.

McQuade A， Kang YJ， Hasselmann J， et al. Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease［J］. Nat Commun， 2020， 11（1）： 5370.

Cai Y， Liu J， Wang B， et al. Microglia in the neuroinflammatory pathogenesis of Alzheimer’s disease and related therapeutic targets［J］. Front Immunol， 2022， 13： 856376.

Wang S， Sudan R， Peng V， et al. TREM2 drives microglia response to amyloid-β via SYK-dependent and-independent pathways［J］. Cell， 2022， 185（22）： 4153-4169. e19.

Zhou Y， Ulland TK， Colonna M. TREM2-dependent effects on microglia in Alzheimer’s disease［J］. Front Aging Neurosci， 2018， 10： 202.

Zheng H， Cheng B， Li Y， et al. TREM2 in Alzheimer’s disease： microglial survival and energy metabolism［J］. Front Aging Neurosci， 2018， 10： 395.

Subhramanyam CS， Wang C， Hu Q， et al. Microglia-mediated neuroinflammation in neurodegenerative diseases［C］ .Semin Cell Dev Biol. Academic Press， 2019， 94： 112-120.

Filipello F， You SF， Mirfakhar FS， et al. Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation［J］. Acta Neuropathol， 2023， 145（6）： 749-772.

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： 113506.

Wang P， Yang P， Qian K， et al. Precise gene delivery systems with detachable albumin shell remodeling dysfunctional microglia by TREM2 for treatment of Alzheimer's disease［J］. Biomaterials， 2022， 281： 121360.

Thal DR， Rüb U， Orantes M， et al. Phases of Aβ-deposition in the human brain and its relevance for the development of AD［J］. Neurology， 2002， 58（12）： 1791-1800.

Ganz T， Fainstein N， Ben-Hur T. When the infectious environment meets the AD brain［J］. Mol Neurodegener， 2022， 17（1）： 53.

Lee CYD， Landreth GE. The role of microglia in amyloid clearance from the AD brain［J］. J Neural Transm （Vienna）， 2010， 117： 949-960.

Fassler M， Rappaport MS， Cuño CB， et al. Engagement of TREM2 by a novel monoclonal antibody induces activation of microglia and improves cognitive function in Alzheimer’s disease models［J］. J Neuroinflammation， 2021， 18： 1-18.

Jain N， Lewis CA， Ulrich JD， et al. Chronic TREM2 activation exacerbates Aβ-associated tau seeding and spreading［J］. J Exp Med， 2022， 220（1）： e20220654.

Zhou Y， Tada M， Cai Z， et al. Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia［J］. Nat Immunol， 2023， 24（3）： 545-557.

Karanfilian L， Tosto MG， Malki K. The role of TREM2 in Alzheimer's disease； evidence from transgenic mouse models［J］. Neurobiol Aging， 2020， 86： 39-53.

Perea JR， Llorens-Martín M， Ávila J， et al. The role of microglia in the spread of tau： relevance for tauopathies［J］. Front Cell Neurosci， 2018， 12： 172.

Perea JR， Bolós M， Avila J. Microglia in Alzheimer’s disease in the context of tau pathology［J］. Biomolecules， 2020， 10（10）： 1439.

Jiang T， Zhang YD， Gao Q， et al. TREM2 ameliorates neuronal tau pathology through suppression of microglial inflammatory response［J］. Inflammation， 2018， 41： 811-823.

Lue LF， Schmitz CT， Serrano G， et al. TREM 2 Protein Expression Changes Correlate with A lzheimer's Disease Neurodegenerative Pathologies in Post‐Mortem Temporal Cortices［J］. Brain Pathol， 2015， 25（4）： 469-480.

Kabir MT， Uddin MS， Mamun AA， et al. Combination drug therapy for the management of Alzheimer’s disease［J］. Int J Mol Sci， 2020， 21（9）： 3272.

Zhu C， Fu S， Chen Y， et al. Advances in drug therapy for Alzheimer’s disease［J］. Curr Med Sci， 2020， 40（6）： 999-1008.

Jiang C， Chen Z， Wang X， et al. Curcumin-activated Olfactory Ensheathing Cells Improve Functional Recovery After Spinal Cord Injury by Modulating Microglia Polarization Through APOE/TREM2/NF-κB Signaling Pathway［J］. J Neuroimmune Pharmacol， 2023， 18（3）： 476-494.

Ren M， Zhang M， Zhang X， et al. Hydroxysafflor Yellow A Inhibits Aβ 1–42-Induced Neuroinflammation by Modulating the Phenotypic Transformation of Microglia via TREM2/TLR4/NF-κB Pathway in BV-2 Cells［J］. Neurochem Res， 2022， 47（3）： 1-14.

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.

Wang S， Mustafa M， Yuede CM， et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model［J］. J Exp Med， 2020， 217（9）： e20200785.

Paul R， Jackson S， Ward M， et al. INVOKE‐2： a phase 2 randomized， double‐blind， placebo‐controlled study to evaluate the efficacy and safety of AL002 in participants with early Alzheimer’s disease［J］. Alzheimer's & Dementia， 2021， 17： e054615.

Melchiorri D， Merlo S， Micallef B， et al. Alzheimer’s disease and neuroinflammation： will new drugs in clinical trials pave the way to a multi-target therapy？［J］. Front Pharmacol， 2023， 14： 1196413.

Yousefizadeh A， Piccioni G， Saidi A， et al. Pharmacological targeting of microglia dynamics in Alzheimer’s disease： preclinical and clinical evidence［J］. Pharmacol Res 2022， 184： 106404.

Rajesh Y， Kanneganti TD. Innate immune cell death in neuroinflammation and Alzheimer’s disease［J］. Cells， 2022， 11（12）： 1885.

徐梦丹. 阿尔茨海默病非药物治疗的研究进展［J］. 中国疗养医学， 2022， 31（6）：590-593.

Xu MD.Research progress in non-pharmacological treatment of Alzheimer's disease ［J］. Chin J Convalescent Med， 2022， 31 （6）： 590-593.

Li X， Ji M， Zhang H， et al. Non-drug therapies for alzheimer’s disease： a review［J］. Neurol Ther， 2023， 12（1）： 39-72.

钟文，申潇竹，许伊雯，等. 阿尔茨海默病非药物治疗的研究进展及展望［J］. 中风与神经疾病杂志， 2023， 40（2）：177-181.

Zhong W， Shen XZ， Xu YW， et al. Research progress and prospects of non pharmacological treatment for Alzheimer's disease ［J］. J Apoplexy Nerv Dis， 2023， 40 （2）： 177-181.

Yoo Y， Neumayer G， Shibuya Y， et al. A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer’s disease［J］. Cell stem cell， 2023， 30（8）： 1043-1053. e6.

Parhizkar S， Gent G， Chen Y， et al. Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice［J］. Sci Transl Med， 2023， 15（693）： eade6285.

Liu G， Zhang L， Fan Y， et al. The pathogenesis in Alzheimer's disease： TREM2 as a potential target［J］. J Integr Neurosci， 2023， 22（6）： 150.

Traikapi A， Konstantinou N. Gamma oscillations in Alzheimer’s disease and their potential therapeutic role［J］. Front Syst Neurosci， 2021， 15： 782399.

Li W， Meng X， Peng K， et al. Boosting microglial lipid metabolism via TREM2 signaling by biomimetic nanoparticles to attenuate the sevoflurane‐induced developmental neurotoxicity［J］. Adv Sci （Weinh）， 2023，11（10）： 2305989.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Effects of Lactobacillus Rhamnosus GG on Activated Microglia and Tau Phosphorylation in the Hippocampus of Aged Mice Induced by Anesthesia and Surgery

Research Progress on Mechanisms of Triggeringreceptor Expressed on Myeloid Cells-2 in Cognitive Dysfunction

Effect of Liquiritigenin on Intestinal Flora in Ovariectomized APP/PS1 Transgenic Mice

Probing the Impact of Whole Intestinal Microbiota Transplantation from Alzheimer's Disease Model Mice on the Ileal Microenvironment Based on the “Interior-Exterior Relationship Exists Between Heart and Small Intestine”

Related Author

LIU Ling

LIU Funing

SHI Limin

XU Ping

YU Hua-rong

HE Gui-qiong

ZHAO Yue-yang

GENG Qing-hua

Related Institution

Department of Anaesthesiology， Sun Yat-sen Memorial Hospital， Sun Yat-sen University

Department of Neurology， Affiliated Hospital of Zunyi Medical University

Department of Physiology of School of Basic Medicine， Chongqing Medical University

Center for Neuroscience Research， Chongqing Medical University

School of Life Science and Engineering， Southwest Jiaotong University

Postal code：510080
Tel：020-87331643，87330827 Email：xbmed@mail.sysu.edu.cn
Technical support is provided by Beijing Founder electronics co., LTD 京ICP备09064830号-19 京公网安备11010802024621
It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.

⁰