Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model
Open accessAbstract
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer's disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.
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Increased sTREM2 inhibits fibrillization of Aβ peptides, increases uptake of Aβ fibrils into microglial cells, and attenuates cognitive and clinical decline in AD patients and AD mouse models.
“Epidemiologic study of AD patients revealed that increased sTREM2 was shown to be beneficial: it can inhibit the fibrillization of Aβ peptides, increase the uptake of Aβ fibrils into microglial cells,235 and attenuate cognitive and clinical decline in AD patients and AD mouse models.236,237”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [237]
The Discussion (page not provided) reports that sTREM2 ameliorated memory deficits in 5×FAD mice, supporting the mouse-model portion. The paper does not report that increased sTREM2 attenuates cognitive or clinical decline in AD patients; its Introduction discusses patient CSF levels, not a clinical benefit. The fibrillization and microglial-uptake clauses are attached to citation 235, rather than this source's citation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLoss of function due to the presence of the Trem2 R47H mutation increases the chance of AD reaching the stage of diagnosis.
“loss of function due to the presence of the Trem2 R47H mutation increasing the chance of AD reaching the stage of diagnosis (44,104–107)”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [105]
Increased expression of TREM2 in Alzheimer's disease has a protective function slowing disease progression.
“Our findings are thus compatible with increased expression of TREM2 in Alzheimer’s disease having a protective function slowing disease progression”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [105]
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Self-citationβ2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function
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“TREM2 is also present as a soluble protein (sTREM2), and most studies have focused on sTREM2 as a potential biomarker for AD progression [19–26], while very few studies have explored sTREM2 biological functions [30, 31, 49, 50].”
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Self-citation
- Authors
- Zhong, L., Xu, Y., Zhuo, R., Wang, T., Wang, K., Huang, R., Wang, D., Gao, Y., Zhu, Y., Sheng, X., Chen, K., Wang, N., Zhu, L., Can, D., Marten, Y., Shinohara, M., Liu, C.-C., Du, D., Sun, H., Wen, L., Xu, H., Bu, G., & Chen, X.-F.
- Affiliations
- Xiamen University (CN)
- Mayo Clinic (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Bu, Guojun
- Chen, Xiao-Fen
- ORCID
- Venue
- Nature Communications
- Published
- 2019-03-25
- Volume
- 10
- Issue
- 1
- Pages
- 1365-1365
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6433910
- OpenAlex
- W2924084484
- Cited by
- 371
- References
- 68
- Citations by year
- 2026: 31 · 2025: 44 · 2024: 59 · 2023: 67 · 2022: 67 · 2021: 38 · 2020: 47 · 2019: 17
- FWCI
- 18.61
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-07-02)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81370459, 81601227, 81373999, 81774377, 31400914, 81701079)
- National Institutes of Health
- Japan Society for the Promotion of Science (16H06277)
- National Institute on Aging (RF1AG056130, R37AG027924, RF1AG056114, R01AG035355)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- soluble TREM2, Alzheimer's disease, microglia, amyloid plaques, amyloid-beta clearance, spatial memory, long-term potentiation, 5xFAD mice, neuroprotection, cerebrospinal fluid biomarkers, AAV gene delivery
- MeSH terms
- Dependovirus, Alzheimer Disease, Animals, Animals, Newborn, Brain, Cell Movement, Disease Models, Animal, Female, Genetic Vectors, Humans, Injections, Intraventricular, Male, Membrane Glycoproteins, Neurons, Peptide Fragments, Phenotype, Receptors, Immunologic, Recombinant Fusion Proteins, Stereotaxic Techniques, Gene Expression, Amyloid beta-Peptides, Microglia, Long-Term Potentiation, Cell Proliferation, Green Fluorescent Proteins, Mice, Plaque, Amyloid, Proteolysis, Primary Cell Culture, Spatial Memory
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