The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease
Open accessAbstract
Neuroinflammation is an important contributor to Alzheimer's disease (AD) pathogenesis, as underscored by the recent identification of immune-related genetic risk factors for AD, including coding variants in the gene TREM2(triggering receptor expressed on myeloid cells 2). Understanding TREM2 function promises to provide important insights into how neuroinflammation contributes to AD pathology. However, studies so far have produced seemingly conflicting results, with reports that amyloid pathology can be both decreased and increased in TREM2-deficient AD mouse models. In this study, we unify these previous findings by demonstrating that TREM2 deficiency ameliorates amyloid pathology early, but exacerbates it late in disease progression in the APPPS1–21 mouse model of AD. We also demonstrate that TREM2 deficiency decreases plaque-associated myeloid cell accumulation by reducing cell proliferation, specifically late in pathology. In addition, TREM2 deficiency reduces myeloid cell internalization of amyloid throughout pathology, but decreases inflammation-related gene transcript levels selectively late in disease progression. Together, these results suggest that TREM2 plays distinct functional roles at different stages in AD pathology. SIGNIFICANCE STATEMENT Alzheimer's disease (AD) is a devastating neurodegenerative disorder and there are currently no effective treatments that modify disease progression. However, the recent identification of genetic risk factors for AD promises to provide new insight into AD biology and possible new therapeutic targets. Among these risk factors, variants in the gene TREM2(triggering receptor expressed on myeloid cells 2) confer greatly elevated risk for developing the disease. We demonstrate that TREM2 deficiency has opposing effects on AD-related pathologies at early and late stages of disease progression, unifying previous work in the field. In addition, we examine how TREM2 affects the function of the brain immune cell populations in which it is expressed throughout disease progression to understand possible mechanisms underlying its differential impacts on pathology.
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In the citing paper
“Using an APP/PS1 AD mouse model, Jay et al. found that TREM2 deficiency reduced Aβ deposition in the young APP/PS1 mice, but exacerbated amyloidopathy in old APP/PS1 mice.228”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [228]
In the citing paper
“A similar interpretation could be developed from the studies of Trem2 deficiency, as differences were dependent on early versus later disease stages.50,51,57,58”
From Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [58]
In the citing paper
“These studies have led to the notion that microglia can have differential effects on AD pathology depending on the disease stage.”
From The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies (2023) · cites this paper as [9]
In the citing paper
“Earlier studies on other microglial AD risk genes reported opposing effects on AD-related pathologies using various animal models at different ages (8–14).”
From The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies (2023) · cites this paper as [9]
In the citing paper
“Conflicting results have been reported regarding amyloid plaque deposition and the effect of TREM2 loss [7,8,9,10,11], suggesting that the effect of TREM2 on Ab deposition may be dependent on age, sex, and the model utilized.”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [8]
In the citing paper
“suggesting that TREM2 deficiency likely affects astrocyte activation rather than the distribution in the brains of mice with amyloid plaques [8].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [8]
In the citing paper
“a decrease in GFAP-positive astrocytes but not S100β-positive astrocytes was observed”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [8]
In the citing paper
“it has been shown that TREM2 downregulation affects the phenotype of GFAP-positive astrocytes in the APP/PS1 amyloid mouse model and the PS19 model of tauopathy [8,13].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [8]
In the citing paper
“TREM2 deletion reduces microglial survival and phagocytosis in vitro and impacts plaque pathology across disease progression in amyloidogenic mouse models.”
From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [42]
In the citing paper
“Murine microglia lacking TREM2 have deficient responses to Aβ and impaired acquisition of the neuroprotective disease‐associated microglia (DAM) phenotype.”
From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [42]
In the citing paper
“the effects of TREM2 depletion depend on the stage of disease progression, in which it ameliorates pathology early and exacerbates it later in the APP PS1‐21 mouse model. 42”
From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [42]
In the citing paper
“On the other hand, another study reported reduced plaque numbers early, but increased plaque area later in disease progression in APP/PS1/Trem2-/- mice [38].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [38]
In the citing paper
“Although Stage 2 DAMs are essential early in AD, they may become dysregulated and ultimately detrimental later in disease progression.44–46”
From TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice (2025) · cites this paper as [45]
In the citing paper
“In AD-like transgenic mice models, TREM2 knockdown is associated with increased amyloid loads [60, 141].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [60]
In the citing paper
“TREM2 has been proposed to be protective, since the AD-associated mutations (R47H, R62H) likely impair its physiological functions at two levels: (1) phagocytosis and clearance of Aβ peptides and (2) compaction of amyloid plaques and barrier formation.”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [60]
In the citing paper
“Studies on TREM2 deficiency in AD mice have produced conflicting results, with reports that Aβ pathology could be either increased or decreased.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [157]
In the citing paper
“Additionally, TREM2 deficiency in aged mice decreased plaque-associated myeloid cell accumulation by reducing proliferation (157).”
From Microglia in Alzheimer's disease (2017) · cites this paper as [157]
In the citing paper
“While TREM2 deficiency in young APP/PS1-21 mice ameliorated amyloid pathology, it enhanced amyloid deposition at later disease stages (157).”
From Microglia in Alzheimer's disease (2017) · cites this paper as [157]
In the citing paper
“Additionally, TREM2 deficiency in aged mice decreased plaque-associated myeloid cell accumulation by reducing proliferation (157).”
From Microglia in Alzheimer's disease (2017) · cites this paper as [157]
In the citing paper
“A recent report indicated that the opposing results from previous work might reflect a disease progression-dependent influence of TREM2 deficiency on AD pathology.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [157]
In the citing paper
“While TREM2 deficiency in young APP/PS1-21 mice ameliorated amyloid pathology, it enhanced amyloid deposition at later disease stages (157).”
From Microglia in Alzheimer's disease (2017) · cites this paper as [157]
In the citing paper
“Trem2 deficiency ameliorated amyloid pathology at early stages but exacerbated it at late stages, suggesting that TREM2 plays distinct roles at different stages of disease175.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [175]
In the citing paper
“References 173–175 show time-dependent differential effects of TREM2-dependent microglial function in AD mouse models.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [175]
In the citing paper
“This concept provides a unifying mechanism to explain the reported broad and long-term impact of TREM2 on diverse microglial functions, such as survival, proliferation, clustering around plaques, as well as phagocytosis of apoptotic cells and myelin debris”
From TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease (2017) · cites this paper as Jay et al., 2017
In the citing paper
“At an early disease stage, the plaque load is reduced in an AD model crossed to Trem2 knockout mouse (Jay et al., 2015), while in more advanced disease stages, the plaque load increased in multiple AD models (Jay et al., 2017; Wang et al., 2015).”
From Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models (2018) · cites this paper as Jay et al., 2017
In the citing paper
“Trem2 deficiency induces dynamic changes but an eventual increase in plaque and neuritic pathology (Jay et al., 2017; Wang et al., 2015; Wang et al., 2016; Yuan et al., 2016).”
From Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models (2018) · cites this paper as Jay et al., 2017
In the citing paper
“For example, we showed several dichotomous cellular and molecular phenotypes between BAC-TREM2 and Trem2-deficient microglia in mouse models of AD (Jay et al., 2017; Ulrich et al., 2017; Yuan et al., 2016). These include the compaction of amyloid plaques, the ramification of plaque-associated microglial processes, the expression of certain activated microglial markers, and phagocytosis.”
From Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models (2018) · cites this paper as Jay et al., 2017
In the citing paper
“TREM2 was recently demonstrated to be essential for promoting microglial cell association with plaques44–49.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [47]
In the citing paper
“Overall, TREM2 deficiency leads to a mild reduction of plaque deposition in early-stage disease, but causes enhanced amyloid-β pathology in advanced stages of the disease45–47.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [47]
In the citing paper
“TREM2 haplodeficiency, ablation, or the TREM2R47H mutation that causes a missense variant of TREM2, eads to a significant reduction of plaque-associated microglia compared to their TREM2-sufficient counterparts44–49.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [47]
In the citing paper
“TREM2−/− amyloid-β depositing mice consistently show downregulation of inflammatory genes, such as Tnf and Il1b45–47, and also of key genes associated with the MGnD phenotype, such as c-type lectin domain family 7 member A (Clec7a) and integrin subunit alpha X (Itgax)27,28”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [47]
In the citing paper
“Supporting this notion, fibrillar plaque staining indicated no difference in the total amount of pathology between TREM2+/+ and TREM2−/− amyloid-β depositing mice at the late stage of disease47.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [47]
In the citing paper
“References 44– 47 show that TREM2 promotes microglial clustering around amyloid-β plaques and demonstrate a disease-stage dependent effect of TREM2 deficiency on amyloid-β pathology.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [47]
In the citing paper
“References 44– 47 show that TREM2 promotes microglial clustering around amyloid-β plaques and demonstrate a disease-stage dependent effect of TREM2 deficiency on amyloid-β pathology.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [47]
In the citing paper
“Partial or completed deletion of TREM2 markedly reduced the number of Aβ-associated macrophages and increased cerebral Aβ plaques in AD model mice.174,175,178”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [178]
Citations
Cites
Neuroinflammation in Alzheimer's disease
Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)70016-5 · Cited by 6,226
Self-citationTREM2 Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020
Variant of TREM2 Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558
Identification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,543
Self-citationNew tools for studying microglia in the mouse and human CNS
Bennett, M. L., Bennett, F. C., Liddelow, S. A., Ajami, B., Zamanian, J. L., Fernhoff, N. B., Mulinyawe, S. B., Bohlen, C. J., Adil, A., Tucker, A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1525528113 · Cited by 1,804
TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model
Wang, Y., Cella, M., Mallinson, K., Ulrich, J. D., Young, K. L., Robinette, M. L., Gilfillan, S., Krishnan, G. M., Sudhakar, S., Zinselmeyer, B. H., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.049 · Cited by 1,736
Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages
Scott, E. W., Simon, M. C., Anastasi, J., & Singh, H. (1994) · Science · doi:10.1126/science.8079170 · Cited by 1,532
Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
Karch, C. M., & Goate, A. M. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.05.006 · Cited by 1,357
Takahashi, K., Rochford, C. D. P., & Neumann, H. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041611 · Cited by 1,124
Aβ42‐driven cerebral amyloidosis in transgenic mice reveals early and robust pathology
Radde, R., Bolmont, T., Kaeser, S. A., Coomaraswamy, J., Lindau, D., Stoltze, L., Calhoun, M. E., Jäggi, F., Wolburg, H., Gengler, S., et al. (2006) · The EMBO Reports · doi:10.1038/sj.embor.7400784 · Cited by 986
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Microglia Function in the Central Nervous System During Health and Neurodegeneration
Colonna, M., & Butovsky, O. (2017) · Annual Review of Immunology · doi:10.1146/annurev-immunol-051116-052358 · Cited by 2,894
Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979
Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., & Jones, D. T. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00269-y · Cited by 2,606
Inflammation as a central mechanism in Alzheimer's disease
Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.06.014 · Cited by 2,253
“[146] Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE, Ransohoff RM, et al.”
BackgroundInfluentialSelf-citationMicroglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935
“Consistent with this notion, plaque accumulation in mouse models of β-amyloidosis (which typically overexpress mutant APP together with mutant PS1 or PS2) is exacerbated at later ages (8+ months) in Trem2 knockout mice (Wang et al., 2015; Jay et al., 2017a).”
Background
Metadata
- Authors
- Jay, T. R., Hirsch, A. M., Broihier, M. L., Miller, C. M., Neilson, L. E., Ransohoff, R. M., Lamb, B. T., & Landreth, G. E.
- Affiliations
- Cleveland Clinic (US)
- Case Western Reserve University (US)
- Biogen (United States) (US)
- Indiana University Indianapolis (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-12-09
- Volume
- 37
- Issue
- 3
- Pages
- 637-647
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5242410
- OpenAlex
- W2560062133
- Cited by
- 457
- References
- 38
- Citations by year
- 2026: 26 · 2025: 42 · 2024: 52 · 2023: 54 · 2022: 43 · 2021: 51 · 2020: 61 · 2019: 40 · 2018: 57 · 2017: 31
- FWCI
- 23.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- Alzheimer's Association (BFG-15-364590)
- Cleveland Clinic
- Case Western Reserve University
- National Institutes of Health
- National Institute on Aging (R01 AG050597, AG050597, F31AG048704, RF1AG051495, AG051495, RF1AG050597)
- National Institute of Neurological Disorders and Stroke (T32NS067431)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- TREM2, Alzheimer's disease, neuroinflammation, amyloid plaques, myeloid cells, disease progression, TREM2 deficiency, myeloid cell proliferation
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Humans, Male, Membrane Glycoproteins, Receptors, Immunologic, Mice, Knockout, Disease Progression, Mice
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