TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation
Open accessAbstract
Background: TREM2 is a transmembrane receptor expressed by myeloid cells and acts to regulate their immune response. TREM2 governs the response of microglia to amyloid and tau pathologies in the Alzheimer’s disease (AD) brain. TREM2 is also present in a soluble form (sTREM2), and its CSF levels fluctuate as a function of AD progression. Analysis of stroke and AD mouse models revealed that sTREM2 proteins bind to neurons, which suggests sTREM2 may act in a non-cell autonomous manner to influence neuronal function. sTREM2 arises from the proteolytic cleavage of the membrane-associated receptor. However, alternatively spliced TREM2 species lacking a transmembrane domain have been postulated to contribute to the pool of sTREM2. Thus, both the source of sTREM2 species and its actions in the brain remain unclear. Methods: The expression of TREM2 isoforms in the AD brain was assessed through the analysis of the Accelerating Medicines Partnership for Alzheimer’s Disease Consortium transcriptomics data, as well as qPCR analysis using post-mortem samples of AD patients and of the AD mouse model 5xFAD. TREM2 cleavage and secretion were studied in vitro using HEK-293T and HMC3 cell lines. Synaptic plasticity, as evaluated by induction of LTP in hippocampal brain slices, was employed as a measure of sTREM2 actions. Results: Three distinct TREM2 transcripts, namely ENST00000373113 (TREM2 230), which encodes the full-length transmembrane receptor, and the alternatively spliced isoforms ENST00000373122 (TREM2 222) and ENST00000338469 (TREM2 219), are moderately increased in specific brain regions of patients with AD. We provide experimental evidence that TREM2 alternatively spliced isoforms are translated and secreted as sTREM2. Furthermore, our functional analysis reveals that all sTREM2 species inhibit LTP induction, and this effect is abolished by the GABAA receptor antagonist picrotoxin. Conclusions: TREM2 transcripts can give rise to a heterogeneous pool of sTREM2 which acts to inhibit LTP. These results provide novel insight into the generation, regulation, and function of sTREM2 which fits into the complex biology of TREM2 and its role in human health and disease. Given that sTREM2 levels are linked to AD pathogenesis and progression, our finding that sTREM2 species interfere with LTP furthers our understanding about the role of TREM2 in AD.
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sTREM2 directly binds to neurons in mouse models of AD and inhibits LTP induction.
“experimental evidence revealed that sTREM2 directly bound to neurons in mouse models of AD194 and inhibited LTP induction.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [195]
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“It is noteworthy that a high-molecular-weight smear is detected for all three sTREM2 species, suggesting robust glycosylation of sTREM2, which has been previously described [12, 47].”
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Self-citationTREM2 brain transcript-specific studies in AD and TREM2 mutation carriers
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“In contrast to our results, a recent RNA-Seq meta-analysis of three AD datasets reported that overall TREM2, TREM2230, and TREM2222 transcripts were not increased in AD, although there was a nominal association between increased expression of TREM2219 and AD cases [16].”
ResultTsai, A. P., Dong, C., Lin, P. B.-C., Messenger, E. J., Casali, B. T., Moutinho, M., Liu, Y., Oblak, A. L., Lamb, B. T., Landreth, G. E., et al. (2022) · Genome Medicine · doi:10.1186/s13073-022-01022-0 · Cited by 92 · cited 2× · see citing works
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Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
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“Soluble TREM2 proteins were quantified by ELISA, similar to what has been previously described [44].”
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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].”
BackgroundSingle-Cell Quantification of mRNA Expression in The Human Brain
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“Changes in the slope of the response (mV/ms) fEPSPs were recorded for 60 min post-induction monitoring at 0.05 Hz.”
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“5, as previously described in detail [40].”
Self-citationTREM2splicing emerges as crucial aspect to understand TREM2 biology
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“TREM2230, TREM2222, and TREM2219 share an identical N-terminal sequence but have distinct C-termini [15].”
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Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
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“195 Together, these novel insights into the function of sTREM2 are important to deepen our understanding of the complex biology of TREM2 and microglia in AD.”
BackgroundInnate immune activation in neurodegenerative diseases
Castro‐Gomez, S., & Heneka, M. T. (2024) · Immunity · doi:10.1016/j.immuni.2024.03.010 · Cited by 167 · see citing works
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“Proteolytic cleavage of the TREM2 ectodomain and/or translation of an alternatively spliced TREM2 transcript [20, 27, 41, 68, 95, 103] are responsible for the production of a soluble form of the receptor (sTREM2) which is detected in the cerebrospinal fluid (CSF) [27, 86].”
BackgroundTREM2 and sTREM2 in Alzheimer’s disease: from mechanisms to therapies
Zhang, L., Xiang, X., Li, Y., Bu, G., & Chen, X. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00834-z · Cited by 78 · see citing works
“Notably, both the ENST00000338469 and ENST00000373122 isoforms are translated and secreted as sTREM2, further supporting the idea that alternative splicing plays a significant role in sTREM2 production [116].”
Wang, L., Nykänen, N.-P., Western, D., Gorijala, P., Timsina, J., Li, F., Wang, Z., Ali, M., Yang, C., Liu, M., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00687-4 · Cited by 58 · see citing works
“This cell line has been used in multiple studies to investigate intracellular TREM2 biology but not sTREM2 derived from HMC3 cells [84–86].”
MethodPocock, J., Vasilopoulou, F., Svensson, E., & Cosker, K. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110020 · Cited by 54 · see citing works
Greven, J. A., Wydra, J. R., Greer, R. A., Zhi, C., Price, D. A., Svoboda, J. D., Camitta, C., Washington, M., Leung, D. W., Song, Y., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00795-9 · Cited by 39 · see citing works
Roles of TREM2 in Alzheimer’s disease
Qi, X., Zhu, K., Ke, W., Wang, J., Mao, S., & Chen, G. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00515-3 · Cited by 36 · see citing works
“In the alternative splicing pathway, specific transcripts (ENST00000373122 and ENST00000338469) undergo selective splicing and the encoded proteins are subsequently secreted into the extracellular space as sTREM2 [75].”
InfluentialHuang, Y.-Y., & Fang, W. (2025) · npj Precision Oncology · doi:10.1038/s41698-025-01152-9 · Cited by 25 · see citing works
Hassan, H., Rawlinson, C., Lan, Y., Jenkins, S. I., & Chen, R. (2025) · Biomolecules · doi:10.3390/biom15111629 · Cited by 24 · see citing works
“Additionally, sTREM2 can bind neurons and inhibit long-term potentiation, negatively impacting cognition [108], highlighting its complex role.”
Lin, C., Kong, Y., Chen, Q., Zeng, J., Pan, X., & Miao, J. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1420731 · Cited by 25 · see citing works
TREM2 variants that cause early dementia and increase Alzheimer’s disease risk affect gene splicing
Kiianitsa, K., Lukes, M. E., Hayes, B. J., Brutman, J. N., Valdmanis, P. N., Bird, T. D., Raskind, W. H., & Korvatska, O. (2024) · Brain · doi:10.1093/brain/awae014 · Cited by 18 · see citing works
Microglial Modulation in Alzheimer’s Disease: Central Players in Neuroinflammation and Pathogenesis
Hussain, M. S., Khan, Y., Fatima, R., Maqbool, M., Ramalingam, P. S., Khan, M. G., & Bisht, A. S. (2025) · Current Alzheimer Research · doi:10.2174/0115672050364292250113063513 · Cited by 15 · see citing works
İş, Ö., Min, Y., Wang, X., Oatman, S. R., Daniel, A. A., & Ertekin‐Taner, N. (2024) · Glia · doi:10.1002/glia.24652 · Cited by 13 · see citing works
Leung, S. K., Bamford, R. A., Jeffries, A. R., Castanho, I., Chioza, B. A., Flaxman, C. S., Moore, K., Dempster, E. L., Harvey, J., Brown, J. T., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50486-8 · Cited by 18 · see citing works
“Of note, a signi fi cant increase of these two Trem2 transcripts was also reported in a recent study using qPCR in two TG amyloid models of AD 22 , suggesting that these transcripts are upregulated in response to both tau and amyloid pathology.”
Lin, N., Zhang, Y., Song, X., Xu, J., Luo, C., Tian, Q. H., Yao, K., Wu, W., Chen, X., & Hu, L. (2023) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2023.126910 · Cited by 8 · see citing works
Glial Cells in Alzheimer’s Disease: Pathogenic Mechanisms and Therapeutic Frontiers
Sil, M., Mukherjee, N., Chatterjee, I., Ghosh, A., & Goswami, A. (2025) · Journal of Molecular Neuroscience · doi:10.1007/s12031-025-02379-8 · Cited by 8 · see citing works
Leung, S. K., Jeffries, A. R., Castanho, I., Bamford, R. A., Moore, K., Dempster, E. L., Brown, J. T., Ahmed, Z., O’Neill, P., Hannon, E. J., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.20.558220 · Cited by 7 · see citing works
Zhou, X., Liu, Z., Li, S., Song, Y., Sun, M., Si, Z., & Zhu, W. (2025) · Inflammation Research · doi:10.1007/s00011-025-02155-9 · Cited by 7 · see citing works
“…shedding by ADAM family proteases or via alternative splicing, and it can be detected in both plasma and cere - brospinal fluid (CSF) [15 , 16 ]. sTREM2, beyond its potential as a biomarker, has exhibited prognostic significance in neurodegenerative disorders, including Parkinson’s…”
The Role of TREM2 After Stroke: From Mechanisms to Therapeutic Potential
Zhou, T., Chen, A., Sun, Y., Huang, B., Xu, Y., & He, Q. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05622-w · Cited by 6 · see citing works
Huang, L., Tan, C., Xu, W., Tan, L., Initiative, A. D. N., Weiner, M. W., Aisen, P. S. S., Petersen, R. C., Jack, C. R., Jagust, W., et al. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03457-6 · Cited by 5 · see citing works
“The extracellular domain of TREM2 can be cleaved to soluble TREM2 (sTREM2) and released into the CSF [11, 12].”
Boreland, A. J., Abbo, Y., Li, X., Stillitano, A. C., Zhang, S., Duan, J., Pang, Z. P., & Hart, R. P. (2025) · Alcohol · doi:10.1016/j.alcohol.2025.10.006 · Cited by 5 · see citing works
The late-onset Alzheimer’s disease risk factor RHBDF2 is a modifier of microglial TREM2 proteolysis
Jocher, G., Müller, S. A., Hsia, H., Osua, M. L., Özcelik, G., Hofmann, L. I., Aßfalg, M., Dinkel, L., Feng, X. M., Schlepckow, K., et al. (2025) · Life Science Alliance · doi:10.26508/lsa.202403080 · Cited by 6 · see citing works
“The remaining sTREM2 in the knock-out cell supernatants may either be proteolytically generated by other proteases, such as ADAM10, or represent soluble, secreted forms of TREM2 that result from alternative splicing of the TREM2 mRNA (Del-Aguila et al, 2019; Moutinho et al, 2023).”
Dempsey, J. L., Savard, C. E., Kothari, V. M., Tang, J., Lee, S. P., Bornfeldt, K., Carr, R. M., & Ioannou, G. N. (2025) · Gastro Hep Advances · doi:10.1016/j.gastha.2025.100828 · Cited by 2 · see citing works
Zhong, Z., Ulmschneider, M. B., & Lorenz, C. D. (2025) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.5c01891 · Cited by 2 · see citing works
Nada, H., Yuan, S., Gaamouch, F. E., Cho, S., & Gabr, M. T. (2026) · European Journal of Medicinal Chemistry Reports · doi:10.1016/j.ejmcr.2026.100354 · Cited by 2 · see citing works
Soluble TREM2 Drives Atherosclerosis via HSP90β-Dependent Myeloid Inflammation
Guo, X., Liu, X., Yu, J., Qin, M., Wang, S., Chen, J., Jiang, D., Feng, Y., Yu, J., Xu, X., et al. (2026) · Circulation Research · doi:10.1161/circresaha.125.327491 · Cited by 2 · see citing works
Chiang, Y.-K., Lin, Y., Chen, C., Lirng, J.-F., Yang, Y., Lee, W., & Fuh, J. (2024) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/15333175241243183 · Cited by 2 · see citing works
“25 One of the few studies addressing the implication of peripheral sTREM2 in AD demonstrated that plasma sTREM2 levels correlate with in fl ammatory activity in the peripheral circulation and vary across different stages of the disease.”
BackgroundPLCG2 signaling and genetic resilience in Alzheimer’s disease
Tsai, A. P., Martin, A. K., Mi, A., Yeh, A. E., Ramirez Lopez, E., & Wyss-Coray, T. (2026) · Molecular Neurodegeneration · doi:10.1186/s13024-026-00935-3
“While variants such as Apolipoprotein E (APOE) ε4 and TREM2 R47H (TREM2 R47H ) are associated with increased AD risk [21, 22], growing attention has shifted toward alleles linked to reduced disease susceptibility that may point to mechanisms of resilience [23].”
Self-citationPottorf, T. S., Lane, E. L., & Álvarez, F. J. (2025) · Cells · doi:10.3390/cells14191520 · Cited by 1 · see citing works
Li, Z., Ming, Q., Fu, L., Yang, J., Lv, Y., Chen, B., & Lu, Z. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1886340 · Cited by 1 · see citing works
“TREM2 splice isoforms generate distinct soluble species that disrupt long-term potentiation (110).”
Ding, D., Zhong, J., Xing, Y., Hu, Y., Ge, X., & Yao, W. (2023) · Current Cancer Drug Targets · doi:10.2174/0115680096266700231107071222 · Cited by 1 · see citing works
Liang, J., Menon, A., Tomco, T., Bhattarai, N., Smith, I. N., Khrestian, M., Formica, S. V., Eng, C., Buck, M., & Bekris, L. M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179667 · Cited by 1 · see citing works
“TREM2 RNA undergoes alternative splicing to generate three TREM2 isoforms in addition to the canonical TREM2 , specifically producing TREM2 △ exon2, TREM2 △ exon4, and TREM2 △ exon5 [7,10].”
BackgroundGreven, J. A., Wydra, J. R., Greer, R. A., Camitta, C., Song, Y., Brett, T. J., & Alexander‐Brett, J. M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.23.595592 · Cited by 1 · see citing works
“Soluble TREM2 (sTREM2) can be produced by proteolytic cleavage [36, 37] or alternative transcripts [38, 39].”
BackgroundYaman, Ü., Banks, G. T., Gustavsson, E. K., Mumford, P., Magusali, N., Taso, O. S., Macpherson, H. L., Carmona, S., Murray, M., Bains, R. S., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.10.607237
Zhong, Z., Ulmschneider, M. B., & Lorenz, C. D. (2025) · bioRxiv · doi:10.1101/2025.06.26.661739
Wang, L., Nykänen, N.-P., Western, D., Gorijala, P., Timsina, J., Li, F., Wang, Z., Ali, M., Yang, C., Liu, M., et al. (2024) · Figshare · doi:10.6084/m9.figshare.24940635
Wang, L., Nykänen, N.-P., Western, D., Gorijala, P., Timsina, J., Li, F., Wang, Z., Ali, M., Yang, C., Liu, M., et al. (2024) · Figshare · doi:10.6084/m9.figshare.24940872
A novel TREM2 L15Q in signal peptide domain and its influence on Aβ pathogenicity
Kim, D., Bae, H., Shim, K. H., Yang, H., Jeong, D.-E., Kang, M. J., & An, S. S. A. (2026) · npj Dementia · doi:10.1038/s44400-025-00057-5
Lietzke, E. E., Saeb, D., Aldrich, E. C., de Menezes, R. F., Bruce, K. D., & Sprenger, K. G. (2026) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2026.06.002 · Cited by 1 · see citing works
Yang, G., Xu, X., & Xu, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1893545
“Given that microglial phenotypes in AD arise from a delicate interplay between lipid metabolism, phagocytosis, and immune signaling, prolonged elevations in sTREM2 may skew microglia toward maladaptive activation states that contribute to synaptic loss or propagate tau pathology (61, 101).”
Identification of RNA-Binding Proteins Regulating the Alternative Splicing of TREM2 Exon 4
Yamada, H., Yanaizu, M., Iwai, N., Kato, M., Suzuki, H., 若井, 瑞., Araki, M., & Kino, Y. (2026) · Genes · doi:10.3390/genes17101188
“This transcript (ENST00000338469) has been detected in the human brain and accounts for approximately 20–25% of total TREM2 mRNA [28,29].”
- Authors
- Moutinho, M., Coronel, I., Tsai, A. P., Di Prisco, G. V., Pennington, T., Atwood, B. K., Puntambekar, S. S., Smith, D. C., Martinez, P., Han, S., Lee, Y., Lasagna-Reeves, C. A., Lamb, B. T., Bissel, S. J., Nho, K., & Landreth, G. E.
- Affiliations
- Indiana University School of Medicine (US)
- Indiana University Indianapolis (US)
- University of Utah (US)
- Corresponding author
- Landreth, Gary E.
- ORCID
- Venue
- Genome Medicine
- Published
- 2023-02-20
- Volume
- 15
- Issue
- 1
- Pages
- 11-11
- ISSN
- 1756-994X (ISSN-L)
- PMC
- PMC9940368
- OpenAlex
- W4321372407
- Cited by
- 42
- References
- 52
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 12 · 2023: 6
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (AG051495, AG076610, AG072177)
- U.S. National Library of Medicine (LM012535)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- TREM2, soluble TREM2, alternative splicing, Alzheimer's disease, long-term potentiation, synaptic plasticity, picrotoxin, GABAA receptor, microglia, 5xFAD mice, cerebrospinal fluid biomarkers
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cell Line, Disease Models, Animal, Humans, Membrane Glycoproteins, Receptors, Immunologic, Long-Term Potentiation, Protein Isoforms, Mice
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