TREM2 ectodomain and its soluble form in Alzheimer’s disease
Open accessAbstract
Triggering receptor expressed on myeloid cells 2 (TREM2) is a receptor mainly expressed on the surface of microglia. It mediates multiple pathophysiological processes in various diseases. Recently, TREM2 has been found to play a role in the development of Alzheimer's disease (AD). TREM2 is a transmembrane protein that is specifically expressed on microglia in the brain. It contains a long ectodomain that directly interacts with the extracellular environment to regulate microglial function. The ectodomain of TREM2 is processed by a disintegrin and metalloprotease, resulting in the release of a soluble form of TREM2 (sTREM2). Recent studies have demonstrated that sTREM2 is a bioactive molecule capable of binding ligands, activating microglia, and regulating immune responses during the AD continuum. Clinical studies revealed that sTREM2 level is elevated in cerebrospinal fluid (CSF) of AD patients, and the sTREM2 level is positively correlated with the levels of classical CSF biomarkers, namely t-tau and p-tau, indicating that it is a reliable predictor of the early stages of AD. Herein, we summarize the key results on the generation, structure, and function of sTREM2 to provide new insights into TREM2-related mechanisms underlying AD pathogenesis and to promote the development of TREM2-based therapeutic strategy.
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TREM2 receptor interaction plays a key role in identifying microglia for the build-up of debris and damage during the regulation of microglial activation.
“TREM2 receptor interaction plays a key role in identifying microglia for the build-up of debris and damage during the regulation of microglial activation.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [202]
TREM2 agonists are being investigated as potential therapeutic agents because they reduce inflammation and encourage amyloid-beta microglial phagocytosis.
“TREM2 agonists are being investigated as potential therapeutic agents since they reduce inflammation and encourage amyloid-beta microglial phagocytosis [202,203,204,205].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [202]
In the healthy aging human brain, amyloid-β plaques have the ability to cause persistent inflammation in microglia.
“In the healthy aging human brain, amyloid-β plaques have the ability to cause persistent inflammation in microglia, which are the brain’s resident immune cells.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [202]
Inflammation, or neuroinflammation, is a crucial factor in the mechanisms behind AD.
“Inflammation, or neuroinflammation, is a crucial factor in the mechanisms behind AD.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [202]
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TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment
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TREM2 expression in the human brain: a marker of monocyte recruitment?
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A Tale of Two Genes: Microglial Apoe and Trem2
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Variable expression of microglial DAP12 and TREM2 genes in Nasu-Hakola disease
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Glial Cell-Mediated Neuroinflammation in Alzheimer’s Disease
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Soluble TREM2: Innocent bystander or active player in neurological diseases?
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Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders
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Neuroinflammation as a Potential Therapeutic Target in Alzheimer’s Disease
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Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease
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Reprogramming of Hepatic Metabolism and Microenvironment in Nonalcoholic Steatohepatitis
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Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease
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“TREM2 agonists are being investigated as potential therapeutic agents since they reduce inflammation and encourage amyloid-beta microglial phagocytosis [202–205].”
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The role of TREM2 in Alzheimer’s disease: from the perspective of Tau
Huang, W., Huang, J., Huang, N., & Luo, Y. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1280257 · Cited by 49 · see citing works
The relationship of soluble TREM2 to other biomarkers of sporadic Alzheimer’s disease
Park, S., Lee, E.-H., Kim, H., Jo, S., Lee, S., Seo, S. W., Park, H.-H., Koh, S., & Lee, J. (2021) · Scientific Reports · doi:10.1038/s41598-021-92101-6 · Cited by 52 · see citing works
Aβ and Tau Regulate Microglia Metabolism via Exosomes in Alzheimer’s Disease
Zhao, Y., Liu, B., Wang, J., Xu, L., Yu, S., Fu, J., Yan, X., & Su, J. (2022) · Biomedicines · doi:10.3390/biomedicines10081800 · Cited by 47 · see citing works
Plasma soluble TREM2 is associated with white matter lesions independent of amyloid and tau
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Does Soluble TREM2 Protect Against Alzheimer's Disease?
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Roles of TREM2 in the Pathological Mechanism and the Therapeutic Strategies of Alzheimer's Disease
Lin, M., Yu, J., Zhang, W., Lao, F., & Huang, H. (2024) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2024.164 · Cited by 41 · see citing works
Abbas, K., Mustafa, M., Alam, M., Habib, S., Ahmad, W., Adnan, M., Hassan, M. I., & Usmani, N. (2025) · Neurogenetics · doi:10.1007/s10048-025-00821-y · Cited by 44 · see citing works
Targeting TREM2 for Parkinson’s Disease: Where to Go?
Li, X., & Zhang, F. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.795036 · Cited by 36 · see citing works
TREM2: Keeping Pace With Immune Checkpoint Inhibitors in Cancer Immunotherapy
Qiu, H., Shao, Z., Wen, X., Jiang, J., Ma, Q., Wang, Y., Huang, L., Ding, X., & Zhang, L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.716710 · Cited by 32 · see citing works
TREM2 in Alzheimer's disease: Structure, function, therapeutic prospects, and activation challenges
Zgórzyńska, E. (2024) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2024.103917 · Cited by 28 · see citing works
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Small molecule therapeutics for neuroinflammation-mediated neurodegenerative disorders
Miller, S., & Blanco, M.-J. (2021) · RSC Medicinal Chemistry · doi:10.1039/d1md00036e · Cited by 21 · see citing works
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Current understanding on TREM-2 molecular biology and physiopathological functions
Bharadwaj, S., Groza, Y., Mierzwicka, J. M., & Malý, P. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112042 · Cited by 22 · see citing works
TREM2 in Neurodegenerative Diseases: Mechanisms and Therapeutic Potential
Li, L., Zheng, X., Ma, H., Zhu, M., Li, X., Sun, X., & Feng, X. (2025) · Cells · doi:10.3390/cells14171387 · Cited by 20 · see citing works
The versatile role of TREM2 in regulating of microglia fate in the ischemic stroke
Ma, W.-Y., Wang, S., Wu, Q.-L., Zhou, X., Chu, S., & Chen, N. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.108733 · Cited by 19 · see citing works
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Microglia Biomarkers in Alzheimer’s Disease
Zhang, P., Hu, H., Tan, L., & Yu, J. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02348-3 · Cited by 18 · see citing works
Hypoxia/ischemia impairs CD33 (Siglec-3)/TREM2 signaling: Potential role in Alzheimer's pathogenesis
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105186 · Cited by 19 · see citing works
Placental DNA methylation changes in gestational diabetes mellitus
Chen, F., Fei, X., Zhu, W., Zhang, Z., Shen, Y., Mao, Y., Zhu, Q., Xu, J., Zhou, W., Li, M., et al. (2022) · Epigenetics · doi:10.1080/15592294.2022.2110193 · Cited by 18 · see citing works
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Regulation of TREM2 on BV2 inflammation through PI3K/AKT/mTOR pathway
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Microglia Process α‐Synuclein Fibrils and Enhance their Pathogenicity in a TREM2‐Dependent Manner
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- Authors
- Yang, J., Fu, Z., Zhang, X., Xiong, M., Meng, L., & Zhang, Z.
- Affiliations
- Renmin Hospital of Wuhan University (CN)
- Corresponding author
- Zhang, Zhentao
- Venue
- Journal of Neuroinflammation
- Published
- 2020-07-07
- Volume
- 17
- Issue
- 1
- Pages
- 204-204
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC7341574
- OpenAlex
- W3039674883
- Cited by
- 113
- References
- 129
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 32 · 2023: 23 · 2022: 19 · 2021: 16
- FWCI
- 1.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (No.81822016,81771382, and 81571249)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, soluble TREM2, Alzheimer's disease, microglia, extracellular domain, cerebrospinal fluid biomarkers, tau protein, early diagnosis, neuroinflammation
- MeSH terms
- Alzheimer Disease, Animals, Humans, Membrane Glycoproteins, Receptors, Immunologic, Solubility, Biomarkers, tau Proteins, Microglia, Protein Isoforms
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