TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy
Open accessAbstract
Significance: Alzheimer’s disease (AD) is the most common cause of dementia and is a major public health problem for which there is currently no disease-modifying treatment. There is an urgent need for greater understanding of the molecular mechanisms underlying neurodegeneration in patients to create better therapeutic options. Recently, genetic studies uncovered novel AD risk variants in the microglial receptor, triggering receptor expressed on myeloid cells 2 (TREM2). Previous studies suggested that loss of TREM2 function worsens amyloid-β (Aβ) plaque-related toxicity. In contrast, we observe TREM2 deficiency mitigates neuroinflammation and protects against brain atrophy in the context of tau pathology. These findings indicate dual roles for TREM2 and microglia in the context of amyloid versus tau pathology, which are important to consider for potential treatments targeting TREM2.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Earlier studies on other microglial AD risk genes reported opposing effects on AD-related pathologies using various animal models at different ages.
“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 [14]
The Discussion (page unavailable) contrasts this study’s protective effect of TREM2 deficiency in a tauopathy mouse model with reports that TREM2 loss worsens amyloid-dependent toxicity in other mouse models. That supports opposing effects across pathologies and models, but the paper does not establish the claim for multiple other microglial AD risk genes or attribute those differences to animals studied at different ages. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn PS19 tau transgenic mice expressing human tau with the P301S mutation (in the absence of plaque pathology), loss of TREM2 was protective against brain atrophy and synapse loss, and this protective effect was abolished in the presence of ApoE4.
“On the other hand, in PS19 tau transgenic mice that express human tau containing the P301S mutation (in the absence of plaque pathology), loss of TREM2 was protective against brain atrophy and synapse loss [41, 42], and this protective effect was abolished in the presence of ApoE4 [43].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [41]
Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredKnockdown of TREM2 alleviates neuroinflammation and prevents neurodegeneration of tau pathology in TREM2−/−PS mice compared with wild-type mice.
“the knockdown of TREM2 could alleviate the neuroinflammation and prevent neurodegeneration of tau pathology in TREM2−/−PS mice compared with wild-type mice (Leyns et al., 2017).”
From AD-Like Neuropsychiatric Dysfunction in a Mice Model Induced by a Combination of High-Fat Diet and Intraperitoneal Injection of Streptozotocin (2024) · cites this paper as Leyns et al., 2017
The Results and Discussion report reduced neuroinflammation and attenuated neurodegeneration in TREM2-deficient PS19 mice compared with TREM2-intact PS19 mice. The claim overstates attenuation as prevention and calls a complete TREM2 knockout a knockdown. The comparator was not non-transgenic wild-type mice. (LLM, conf=0.86)
Experimental — accuracy not yet measuredManipulation of Trem2, Tyrobp, Cx3cl1/Cx3cr1, IL1β, and IFN-γ have opposing effects on amyloid and tau pathologies.
“Indeed, manipulation of expression of Trem2, Tyrobp, Cx3cl1/Cx3cr1, IL1β, and IFN-γ have all been shown to have opposing effects on amyloid and tau pathologies [49–51, 55–65].”
From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [50]
The Discussion (page unavailable) describes opposing consequences of TREM2 deficiency: greater amyloid-dependent toxicity but less neurodegeneration in the tauopathy model. It also says tau deposition was not detectably changed in that model, so the contrast is not an opposing effect on amyloid and tau pathology themselves. The paper does not establish the claimed opposing effects for Tyrobp, Cx3cl1/Cx3cr1, IL-1β, or IFN-γ; its Results report reduced IL-1β expression after TREM2 deficiency, not manipulation of IL-1β. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTrem2 deficiency attenuates neurodegeneration in Tau transgenic mice and seems to reduce the neuroinflammatory response.
“Trem2 deficiency attenuates neurodegeneration in Tau transgenic mice and seems to reduce the neuroinflammatory response [146].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [146]
Microglia can have differential effects on Alzheimer's disease pathology depending on the disease stage.
“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 [14]
TREM2 ablation was protective and decreased synaptic impairment and neurodegenerative phenotypes in the PS19 mouse model.
“However, TREM2 ablation was protective and decreased synaptic impairment and neurodegenerative phenotypes [13] in the PS19 mouse model [17].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [13]
Collectively, studies yielded disparate results regarding the effect of TREM2 on tau pathology and whether the effect is amyloid dependent or independent.
“Collectively, these studies yielded disparate results regarding the effect of TREM2 on tau pathology and whether the effect is amyloid dependent or independent.”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [13]
TREM2 loss-of-function studies have yielded conflicting outcomes in the context of tau pathology.
“TREM2 loss-of-function studies have also yielded conflicting outcomes in the context of tau pathology.”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [13]
In PS19 mice crossed with Trem2 KO mice, brain atrophy and microgliosis were reduced.
“brain atrophy and microgliosis were reduced [13].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [13]
Total deletion of TREM2 did not affect tau pathology in PS19 mice crossed with Trem2 KO mice.
“total deletion of TREM2 did not affect tau pathology in PS19 mice crossed with Trem2 KO mice”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [13]
In PS19 mice, there were no differences in microglia proliferation regardless of Trem2 genotype.
“The authors did not observe differences in microglia proliferation in PS19 mice regardless of Trem2 genotype”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [13]
In PS19 mice, a decrease in inflammatory transcripts was observed due to TREM2 ablation.
“a decrease in inflammatory transcripts was observed in PS19 mice due to TREM2 ablation”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [13]
TREM2 downregulation affects the phenotype of GFAP-positive astrocytes in the APP/PS1 amyloid mouse model and the PS19 model of tauopathy.
“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 [13]
TREM2-deficient microglia may undergo metabolic stress, impacting their function and capacity to respond to damage incited by tauopathy, possibly leading to inadvertent cell death.
“suggesting that TREM2-deficient microglia may undergo metabolic stress, impacting their function and capacity to respond to damage incited by tauopathy, possibly leading to inadvertent cell death [13].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [13]
Ablation of TREM2 in the PS19 mouse model decreased the number of IBA1-positive microglia in regions affected by tau pathology.
“the ablation of TREM2 in the PS19 mouse model decreased the number of IBA1-positive microglia in regions affected by tau pathology [13]”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [13]
Loss of TREM2 function impacts microglial activation, hindering inflammatory responses.
“suggesting that loss of TREM2 function impacts microglial activation, hindering inflammatory responses [13].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [13]
TREM2 deficiency protects against tau-associated neurodegeneration in P301S mice.
“Interestingly, TREM2 deficiency also protects against tau-associated neurodegeneration in P301S mice (Leyns et al., 2017).”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Leyns et al., 2017
The dichotomy of immune effects on amyloid and tau has been demonstrated in multiple models of Trem2 and Tyrobp.
“More recently, this dichotomy has been elegantly demonstrated in multiple models of Trem2 and Tyrobp [49–51, 55–59].”
From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [50]
In tau-P301S transgenic mice, TREM2 deletion attenuates neuroinflammation and protects against neurodegeneration at a late stage without altering tau phosphorylation and aggregation.
“In contrast, in tau-P301S transgenic mice, TREM2 deletion attenuates neuroinflammation and protects against neurodegeneration at a late stage without altering tau phosphorylation and aggregation [127].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [127]
TREM2 deficiency significantly reduces brain atrophy and prevents microglial activation in tau transgenic mice.
“other studies found that TREM2 deficiency significantly reduced brain atrophy and prevented microglial activation in tau transgenic mice.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [178]
In the tau model of neurodegeneration, genetic deletion of either Apoe or Trem2 arrested neurodegeneration, demonstrating that this pathway negatively regulates the homeostatic signature.
“In the tau model of neurodegeneration, genetic deletion of either Apoe or Trem2 also arrested neurodegeneration, demonstrating that this pathway negatively regulates the homeostatic signature182,183.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [183]
TREM2 and ApoE signalling are linked to worsened neuroinflammation and tauopathy.
“References 182 and 183 connect TREM2 and ApoE signalling with exacerbation of neuroinflammation and tauopathy.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [183]
TREM2 deficiency enhances tau hyperphosphorylation at an early disease stage in htau mice and a mid-disease stage in P301S mice, but does not affect tau pathology at a late-disease stage in P301S mice.
“TREM2 deficiency is reported to enhance tau hyperphosphorylation at an early disease stage in htau mice65 and a mid-disease stage in P301S mice [G]66, but does not affect tau pathology at a late-disease stage in P301S mice67”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [67]
End-stage TREM2−/− P301S mice that exhibit significantly reduced microgliosis and downregulated MGnD genes such as ApoE and Cst7, show significantly attenuated brain atrophy compared to TREM2+/+ P301S mice despite no change of tau pathology.
“End-stage TREM2−/− P301S mice that exhibit significantly reduced microgliosis and downregulated MGnD genes such as ApoE and cystatin 7 (Cst7), show significantly attenuated brain atrophy compared to TREM2+/+ P301S mice despite no change of tau pathology67.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [67]
Targeting TREM2 signaling in the facial nerve axotomy model ameliorates neuronal loss, and ablation of TREM2 in tauopathy mice attenuates neuroinflammation and neurodegeneration, similar to the effect of ApoE deletion.
“Targeting TREM2 signaling in the facial nerve axotomy model ameliorates neuronal loss28, and ablation of TREM2 in tauopathy mice attenuates neuroinflammation and neurodegeneration67, similar to the effect of ApoE deletion.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [67]
Dampening neurodegenerative microglial activation via TREM2 deletion reduces neurodegeneration at an advanced disease stage in a tauopathy mouse model.
“This work shows that dampening neurodegenerative microglial activation via TREM2 deletion reduces neurodegeneration at an advanced disease stage in a tauopathy mouse model, supporting a role of microglia in modulating neurodegeneration.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [67]
Microglia modulate neurodegeneration.
“This work shows that dampening neurodegenerative microglial activation via TREM2 deletion reduces neurodegeneration at an advanced disease stage in a tauopathy mouse model, supporting a role of microglia in modulating neurodegeneration.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [67]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859 · see citing works
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971 · cited 1× · see citing works
“Recent studies have further demonstrated that microglia can influence astrocyte reactivity in several disease models (34, 35).”
BackgroundA Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493 · see citing works
Self-citation<i>TREM2</i> 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 · see citing works
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 · see citing works
Self-citationVariant of <i>TREM2</i> 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 · cited 1× · see citing works
“The discovery that rare coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with a twofold to fourfold increased risk for developing sporadic, lateonset AD further implicates the role of microglia in AD (6, 7).”
BackgroundSynapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.010 · Cited by 2,208 · see citing works
How neuroinflammation contributes to neurodegeneration
Ransohoff, R. M. (2016) · Science · doi:10.1126/science.aag2590 · Cited by 1,967 · cited 1× · see citing works
“Chronic microglial activation has been hypothesized to lead to excessive neuroinflammation that may exacerbate AD pathologies and neurodegeneration (43).”
BackgroundTREM2 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 · see citing works
Self-citationAlzheimer’s Disease: The Challenge of the Second Century
Holtzman, D. M., Morris, J. C., & Goate, A. M. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002369 · Cited by 1,424 · cited 1× · see citing works
“Amyloid-β (Aβ) aggregates form extracellular plaques, while hyperphosphorylated tau (p-tau) is present in intracellular neurofibrillary tangles (1).”
BackgroundSelf-citationRole of pro-inflammatory cytokines released from microglia in Alzheimer's disease.
(2015) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2305-5839.2015.03.49 · Cited by 1,288 · cited 1× · see citing works
“Analysis of human AD brain tissue has revealed up-regulation of several inflammatory cytokines in areas of dense tangle pathology and gliosis in AD and other tauopathies (44, 45).”
BackgroundTREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease
Ulland, T. K., Song, W. M., Huang, S. C.-C., Ulrich, J. D., Sergushichev, A., Beatty, W. L., Loboda, A. A., Zhou, Y., Cairns, N. J., Kambal, A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.023 · Cited by 1,263 · cited 1× · see citing works
“A recent report further detailed that deficits in cellular metabolism lead to accumulation of autophagic bodies in Trem2 microglia and are responsible for decreasing microglial health (40).”
BackgroundSelf-citationInflammation in Neurodegenerative Disease—A Double-Edged Sword
Wyss-Coray, T., & Mucke, L. (2002) · Neuron · doi:10.1016/s0896-6273(02)00794-8 · Cited by 1,235 · see citing works
ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy
Initiative, A. D. N., Shi, Y., Yamada, K., Liddelow, S. A., Smith, S. T., Zhao, L., Luo, W., Tsai, R. M., Spina, S., Grinberg, L. T., et al. (2017) · Nature · doi:10.1038/nature24016 · Cited by 1,220 · cited 6× · see citing works
“Although the exact molecular effects of AD-associated risk variants in TREM2 are still being investigated, the most common position 47 arginine-to-histidine (R47H) variant appears to reduce binding to anionic phospholipids, including binding to apolipoproteins such as ApoE, and reduce lipid-induced TREM2 activity (9–1…”
BackgroundResultInfluentialSelf-citationMicroglial Activation and Chronic Neurodegeneration
Lull, M. E., & Block, M. L. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2010.05.014 · Cited by 1,047 · cited 1× · see citing works
“Analysis of human AD brain tissue has revealed up-regulation of several inflammatory cytokines in areas of dense tangle pathology and gliosis in AD and other tauopathies (44, 45).”
BackgroundAugustinack, J. C., Schneider, A., Mandelkow, E.-M., & Hyman, B. T. (2002) · Acta Neuropathologica · doi:10.1007/s004010100423 · Cited by 998 · cited 1× · see citing works
“The tau monoclonal antibody, AT8, recognizes a double phosphorylation epitope (pS202, pT205) and has been shown to primarily stain intraneuronal and extraneuronal neurofibrillary tangles associated with Braak stages IV, V, and VI (24).”
BackgroundYeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C., & Sheng, M. (2016) · Neuron · doi:10.1016/j.neuron.2016.06.015 · Cited by 943 · see citing works
Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease
Itagaki, S., McGeer, P. L., Akiyama, H., Zhu, S., & Selkoe, D. (1989) · Journal of Neuroimmunology · doi:10.1016/0165-5728(89)90115-x · Cited by 940 · cited 4× · see citing works
“Reactive microglia have been described in brain regions affected by a high density of tau tangles both in AD as well as in other primary tauopathies such as FTD (2, 5, 25).”
BackgroundInfluentialTREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
Wang, Y., Ulland, T. K., Ulrich, J. D., Song, W., Tzaferis, J. A., Hole, J. T., Yuan, P., Mahan, T. E., Shi, Y., Gilfillan, S., et al. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20151948 · Cited by 840 · see citing works
Self-citationYuan, P., Condello, C., Keene, C. D., Wang, Y., Bird, T. D., Paul, S. M., Luo, W., Colonna, M., Baddeley, D., & Grutzendler, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.05.003 · Cited by 817 · see citing works
Self-citationApolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
Holtzman, D. M., Herz, J., & Bu, G. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006312 · Cited by 782 · cited 1× · see citing works
“While Cst7 is a microgliaspecific gene (32), Apoe is expressed by both astrocytes and microglia in the brain (33).”
BackgroundSelf-citationTREMs in the immune system and beyond
Colonna, M. (2003) · Nature Reviews Immunology · doi:10.1038/nri1106 · Cited by 701 · cited 1× · see citing works
“However, TREM2 has classically been described as modestly antiinflammatory and loss of function has also been shown to reduce the same inflammatory markers, such as IL-1β and TNF-α, in other studies (21, 39).”
BackgroundSelf-citationThree dimensions of the amyloid hypothesis: time, space and 'wingmen'
Musiek, E. S., & Holtzman, D. M. (2015) · Nature Neuroscience · doi:10.1038/nn.4018 · Cited by 697 · cited 1× · see citing works
“AD pathology is characterized first by the appearance of Aβ plaques followed by the spread of neurofibrillary tau tangles from the transentorhinal region, to the hippocampus, and into the neocortex (15).”
BackgroundSelf-citationCutting Edge: TREM-2 Attenuates Macrophage Activation
Turnbull, I. R., Gilfillan, S., Cella, M., Aoshi, T., Miller, M., Piccio, L., Hernandez, M., & Colonna, M. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.6.3520 · Cited by 688 · cited 2× · see citing works
“However, TREM2 has classically been described as modestly antiinflammatory and loss of function has also been shown to reduce the same inflammatory markers, such as IL-1β and TNF-α, in other studies (21, 39).”
BackgroundSelf-citationJay, T. R., Miller, C. M., Cheng, P. J., Graham, L. C., Bemiller, S., Broihier, M. L., Xu, G., Margevicius, D., Karlo, J. C., Sousa, G. L., et al. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20142322 · Cited by 682 · see citing works
Early Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain
Ingelsson, M., Fukumoto, H., Newell, K. L., Growdon, J. H., Hedley–Whyte, E. T., Frosch, M. P., Albert, M. S., Hyman, B. T., & Irizarry, M. C. (2004) · Neurology · doi:10.1212/01.wnl.0000115115.98960.37 · Cited by 666 · cited 1× · see citing works
“The amount of reactive gliosis in human AD patient brains has been reported to more closely correlate with the degree of neurofibrillary tangle pathology as opposed to amyloid plaque burden (26, 27).”
BackgroundApolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
Atagi, Y., Liu, C.-C., Painter, M. M., Chen, X.-F., Verbeeck, C., Zheng, H., Li, X., Rademakers, R., Kang, S. S., Xu, H., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.679043 · Cited by 587 · see citing works
Yanamandra, K., Kfoury, N., Jiang, H., Mahan, T. E., Ma, S., Maloney, S. E., Wozniak, D. F., Diamond, M. I., & Holtzman, D. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.046 · Cited by 574 · cited 2× · see citing works
“In this study, we only examined male mice as there is significantly more tau pathology and neurodegeneration in male versus female PS19 mice (23).”
BackgroundSelf-citationReactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer’s Disease
Serrano-Pozo, A., Mielke, M. L., Gómez-Isla, T., Betensky, R. A., Growdon, J. H., Frosch, M. P., & Hyman, B. T. (2011) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.05.047 · Cited by 488 · cited 2× · see citing works
“3 at 1:200 and anti-Tau5 (27) were used.”
BackgroundDisease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease
Jay, T. R., Hirsch, A. M., Broihier, M. L., Miller, C. M., Neilson, L. E., Ransohoff, R. M., Lamb, B. T., & Landreth, G. E. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2110-16.2016 · Cited by 457 · see citing works
Glial contributions to neurodegeneration in tauopathies
Leyns, C. E. G., & Holtzman, D. M. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0192-x · Cited by 409 · cited 9× · see citing works
“Chronic microgliosis has long been hypothesized to influence accumulation of Aβ and tau, contribute to neuronal damage, and ultimately exacerbate neurodegeneration (4, 5).”
BackgroundInfluentialSelf-citationButovsky, O., Jedrychowski, M. P., Cialic, R., Krasemann, S., Murugaiyan, G., Fanek, Z., Greco, D. J., Wu, P. M., Doykan, C. E., Kiner, O., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24304 · Cited by 358 · see citing works
Soluble TREM2 induces inflammatory responses and enhances microglial survival
Zhong, L., Chen, X., Wang, T., Wang, Z., Liao, C., Wang, Z., Huang, R., Wang, D., Li, X., Wu, L., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20160844 · Cited by 358 · cited 1× · see citing works
“This may be facilitated by mechanistic in vitro studies, further analysis of mouse models, and examining soluble TREM2 fragments detectable in human cerebral spinal fluid throughout the course of AD (46, 47).”
BackgroundTREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury
Mazaheri, F., Snaidero, N., Kleinberger, G., Madore, C., Daria, A., Werner, G., Krasemann, S., Capell, A., Trümbach, D., Wurst, W., et al. (2017) · The EMBO Reports · doi:10.15252/embr.201743922 · Cited by 351 · cited 1× · see citing works
“For instance, decreased neuroinflammatory markers in TREM2-deficient stroke, traumatic brain injury, and neuropathic pain models may result from impaired chemotaxis following neuronal injury (30) and decreased microglial activation (36–38).”
BackgroundUntangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses
Srinivasan, K., Friedman, B. A., Larson, J. L., Lauffer, B. E., Goldstein, L. D., Appling, L. L., Borneo, J., Poon, C., Ho, T., Cai, F., et al. (2016) · Nature Communications · doi:10.1038/ncomms11295 · Cited by 336 · cited 1× · see citing works
“While Cst7 is a microgliaspecific gene (32), Apoe is expressed by both astrocytes and microglia in the brain (33).”
BackgroundElucidating the Role of TREM2 in Alzheimer’s Disease
Ulrich, J. D., Ulland, T. K., Colonna, M., & Holtzman, D. M. (2017) · Neuron · doi:10.1016/j.neuron.2017.02.042 · Cited by 325 · cited 3× · see citing works
“However, the effects of TREM2 deficiency on overall plaque load have been variable (8).”
BackgroundInfluentialSelf-citationTREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway
Zheng, H., Jia, L., Liu, C.-C., Rong, Z., Zhong, L., Yang, L., Chen, X.-F., Fryer, J. D., Wang, X., Zhang, Y.-W., et al. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2459-16.2017 · Cited by 317 · cited 1× · see citing works
“Recent studies provided further evidence that TREM2 promotes microglial survival via the Wnt/β-catenin signaling pathway (41, 42).”
BackgroundOtero, K., Turnbull, I. R., Poliani, P. L., Vermi, W., Cerutti, E., Aoshi, T., Tassi, I., Takai, T., Stanley, S. L., Miller, M., et al. (2009) · Nature Immunology · doi:10.1038/ni.1744 · Cited by 315 · see citing works
Self-citationThe Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E
Bailey, C. C., DeVaux, L. B., & Farzan, M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.677286 · Cited by 303 · see citing works
Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2
Ulrich, J. D., Finn, M. B., Wang, Y., Shen, A., Mahan, T. E., Jiang, H., Stewart, F. R., Piccio, L., Colonna, M., & Holtzman, D. M. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-20 · Cited by 302 · see citing works
Self-citationSong, W., Hooli, B., Mullin, K., Jin, S. C., Cella, M., Ulland, T. K., Wang, Y., Tanzi, R. E., & Colonna, M. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.07.004 · Cited by 297 · see citing works
Self-citationSuárez-Calvet, M., Araque Caballero, M. Á., Kleinberger, G., Bateman, R. J., Fagan, A. M., Morris, J. C., Levin, J., Danek, A., Ewers, M., Haass, C., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aag1767 · Cited by 272 · cited 1× · see citing works
“This may be facilitated by mechanistic in vitro studies, further analysis of mouse models, and examining soluble TREM2 fragments detectable in human cerebral spinal fluid throughout the course of AD (46, 47).”
BackgroundKober, D. L., Alexander-Brett, J. M., Karch, C. M., Cruchaga, C., Colonna, M., Holtzman, M. J., & Brett, T. J. (2016) · eLife · doi:10.7554/elife.20391 · Cited by 238 · see citing works
Self-citationYuan, P., Condello, C., Keene, C. D., Wang, Y., Bird, T. D., Paul, S. M., Luo, W., Colonna, M., Baddeley, D., & Grutzendler, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.09.016 · Cited by 219 · cited 4× · see citing works
“to increased neuritic dystrophy and p-tau accumulation around plaques in Trem2-deficient mouse models and in human R47H variant carriers (19, 20).”
BackgroundResultInfluentialSelf-citationTREM2/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain
Kobayashi, M., Konishi, H., Sayo, A., Takai, T., & Kiyama, H. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1238-16.2016 · Cited by 160 · see citing works
Sieber, M. W., Jaenisch, N., Brehm, M., Guenther, M., Linnartz‐Gerlach, B., Neumann, H., Witte, O., & Frahm, C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0052982 · Cited by 136 · see citing works
Sheffield, L. G., Marquis, J. G., & Berman, N. E. J. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)01037-5 · Cited by 96 · cited 1× · see citing works
“Microgliosis, or activation of the innate immune cells in the brain, is an additional pathological signature routinely found in regions affected by abundant plaques and tangles (2, 3).”
BackgroundSaber, M., Kokiko‐Cochran, O. N., Puntambekar, S. S., Lathia, J. D., & Lamb, B. T. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2016.4401 · Cited by 95 · cited 1× · see citing works
“Trem2mice had reduced levels of inflammatory transcripts, less hippocampal atrophy, and rescue of behavioral deficits 120 d after traumatic brain injury (36).”
BackgroundBellucci, A., Bugiani, O., Ghetti, B. F., & Spillantini, M. G. (2011) · Neurodegenerative Diseases · doi:10.1159/000322228 · Cited by 88 · cited 3× · see citing works
“Reactive microglia have been described in brain regions affected by a high density of tau tangles both in AD as well as in other primary tauopathies such as FTD (2, 5, 25).”
BackgroundAAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy
Ising, C., Gallardo, G., Leyns, C. E. G., Wong, C. H., Jiang, H., Stewart, F., Koscal, L. J., Roh, J., Robinson, G. O., Remolina Serrano, J., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20162125 · Cited by 57 · cited 3× · see citing works
“quantified in a tau sandwich ELISA as previously described (48) using Tau-5 as”
MethodInfluentialSelf-citation
Flagged first, then by citations
Cited by
Sorted by citations
Scheltens, P., De Strooper, B., Kivipelto, M., Holstege, H., Chételat, G., Teunissen, C. E., Cummings, J., & van der Flier, W. M. (2021) · The Lancet · doi:10.1016/s0140-6736(20)32205-4 · Cited by 5,465 · see citing works
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204 · see citing works
Self-citationInflammation 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 · see citing works
“The Holtzman group recently reported mitigated neuroinflammation, astrocytosis, and reduced neurodegeneration at advanced ages in the PS19 mouse model of tauopathy, an aggressive model of tauopathy harboring the FTD-associated P301S 4R familial tau mutation [157].”
BackgroundMicroglia 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 · see citing works
“, 2017); however, this is debatable, because TREM2 facilitates neurodegeneration in the PS19 model (Leyns et al., 2017) and is presumably required for the up-regulation of DAM genes in that model (Friedman et al.”
BackgroundInfluentialMicroglia in neurodegeneration
Hickman, S., Izzy, S., Sen, P., Morsett, L., & El Khoury, J. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0242-x · Cited by 1,710 · see citing works
Role of neuroinflammation in neurodegeneration development
Zhang, W., Xiao, D., Mao, Q., & Xia, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01486-5 · Cited by 1,668 · see citing works
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
Gao, C., Jiang, J., Tan, Y., & Chen, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01588-0 · Cited by 1,616 · see citing works
“Responding to tau pathology, in the early stages of AD, TREM2 may suppress tau seeding, but later in AD, it may aggravate tau propagation.(178,179,181,182) Fig.”
BackgroundDisease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., & Amit, I. (2018) · Cell · doi:10.1016/j.cell.2018.05.003 · Cited by 1,474 · see citing works
Self-citationMicroglial signatures and their role in health and disease
Butovsky, O., & Weiner, H. L. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0057-5 · Cited by 1,046 · see citing works
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
“However, TREM2 deletion does not affect tau phosphorylation and aggregation in tau P301S transgenic PS19 mice, but alleviates gliosis and brain atrophy at 9 months of age [347].”
BackgroundReconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease
Kametani, F., & Hasegawa, M. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00025 · Cited by 836 · see citing works
“Indeed, it was recently shown that the AD risk factors ApoE4 and TREM2 are linked to tau pathology (Bemiller et al., 2017; Leyns et al., 2017; Shi et al., 2017).”
BackgroundTREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge
Nugent, A. A., Lin, K., van Lengerich, B., Lianoglou, S., Przybyla, L., Davis, S. S., Llapashtica, C., Wang, J., Kim, D. J., Xia, D., et al. (2020) · Neuron · doi:10.1016/j.neuron.2019.12.007 · Cited by 745 · see citing works
TREM2 — a key player in microglial biology and Alzheimer disease
Ulland, T. K., & Colonna, M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0072-1 · Cited by 735 · see citing works
Self-citationMicroglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response
Bachiller, S., Jiménez-Ferrer, I., Paulus, A., Yang, Y., Swanberg, M., Deierborg, T., & Boza‐Serrano, A. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00488 · Cited by 706 · see citing works
Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight
Shi, Y., & Holtzman, D. M. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0051-1 · Cited by 595 · see citing works
Self-citationAmyloid-β-independent regulators of tau pathology in Alzheimer disease
van der Kant, R., Goldstein, L. S. B., & Ossenkoppele, R. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0240-3 · Cited by 580 · see citing works
Wang, C., & Holtzman, D. M. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0478-5 · Cited by 589 · see citing works
Self-citationNew insights into the role of TREM2 in Alzheimer’s disease
Gratuze, M., Leyns, C. E. G., & Holtzman, D. M. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0298-9 · Cited by 489 · see citing works
Self-citationTau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation
Chen, Y., & Yu, Y. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02853-3 · Cited by 516 · see citing works
“In contrast, in tau-P301S transgenic mice, TREM2 deletion attenuates neuroinflammation and protects against neurodegeneration at a late stage without altering tau phosphorylation and aggregation [127].”
BackgroundMicroglia drive APOE-dependent neurodegeneration in a tauopathy mouse model
Shi, Y., Manis, M., Long, J., Wang, K., Sullivan, P. M., Remolina Serrano, J., Hoyle, R., & Holtzman, D. M. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20190980 · Cited by 448 · see citing works
“While both microglia and astrocytes are immune competent, accumulating genetic and functional evidence suggests that microglia, the brain-resident professional immune cells, may play a major role in regulating innate immunity-induced neurodegeneration (Leyns et al., 2017; Pimenova et al., 2018).”
Self-citationInflammation: the link between comorbidities, genetics, and Alzheimer’s disease
Newcombe, E. A., Camats-Perna, J., Silva, M. L., Valmas, N., Huat, T. J., & Medeiros, R. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1313-3 · Cited by 532 · see citing works
Lee, C. Y. D., Daggett, A., Gu, X., Jiang, L.-L., Langfelder, P., Li, X., Wang, N., Zhao, Y., Park, C. S., Cooper, Y., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.02.002 · Cited by 396 · see citing works
“in two tauopathy mouse models (Bemiller et al., 2017; Leyns et al., 2017), which are reminiscent of those observed in the APP models (Jay et al.”
BackgroundAlzheimer’s disease: insights into pathology, molecular mechanisms, and therapy
Zheng, Q., & Wang, X. (2024) · Protein & Cell · doi:10.1093/procel/pwae026 · Cited by 454 · see citing works
TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease
Griciuc, A., Patel, S., Federico, A. N., Choi, S. H., Innes, B. J., Oram, M. K., Cereghetti, G., McGinty, D., Anselmo, A., Sadreyev, R. I., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.06.010 · Cited by 378 · see citing works
“In a tauopathy mouse model, TREM2 knock-out reduced pro-inflammatory microglial activation, but ameliorated neurodegeneration (Leyns et al., 2017).”
Self-citationRodent models for Alzheimer disease
Götz, J., Bodea, L., & Goedert, M. (2018) · Nature reviews. Neuroscience · doi:10.1038/s41583-018-0054-8 · Cited by 395 · see citing works
Colonna, M. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00837-1 · Cited by 394 · see citing works
Self-citationEmerging diagnostics and therapeutics for Alzheimer disease
Self, W. K., & Holtzman, D. M. (2023) · Nature Medicine · doi:10.1038/s41591-023-02505-2 · Cited by 381 · see citing works
Self-citationThe complexity of tau in Alzheimer’s disease
Naseri, N. N., Wang, H., Guo, J. D., Sharma, M., & Luo, W. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.04.022 · Cited by 374 · see citing works
TREM2 function impedes tau seeding in neuritic plaques
Leyns, C. E. G., Gratuze, M., Narasimhan, S., Jain, N., Koscal, L. J., Jiang, H., Manis, M., Colonna, M., Lee, V. M. Y., Ulrich, J. D., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0433-0 · Cited by 332 · see citing works
Self-citationMicroglia: Agents of the CNS Pro-Inflammatory Response
Rodríguez-Gómez, J. A., Kavanagh, E., Engskog-Vlachos, P., Engskog, M. K. R., Herrera, A. J., Espinosa-Oliva, A. M., Joseph, B., Hajji, N., Venero, J. L., & Burguillos, M. A. (2020) · Cells · doi:10.3390/cells9071717 · Cited by 365 · see citing works
McQuade, A., Kang, Y. J., Hasselmann, J., Jairaman, A., Sotelo, A., Coburn, M., Shabestari, S. K., Chadarevian, J. P., Fote, G., Tu, C. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19227-5 · Cited by 361 · see citing works
Boza-Serrano, A., Ruiz, R., Sanchez-Varo, R., García-Revilla, J., Yang, Y., Jimenez-Ferrer, I., Paulus, A., Wennström, M., Vilalta, A., Allendorf, D., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02013-z · Cited by 357 · see citing works
Ewers, M., Franzmeier, N., Suárez-Calvet, M., Morenas-Rodriguez, E., Caballero, M. A. A., Kleinberger, G., Piccio, L., Cruchaga, C., Deming, Y., Dichgans, M., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aav6221 · Cited by 327 · see citing works
“However, a recent study reported beneficial effects of TREM2 deficiency in a transgenic mouse model of tauopathy ( 50 ).”
Immune Signaling in Neurodegeneration
Hammond, T. R., Marsh, S. E., & Stevens, B. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.016 · Cited by 336 · see citing works
“While one report found that Trem2-KO reduced brain atrophy but had no impact on tau pathology when crossed to the PS19 transgenic tau model (Leyns et al., 2017), another report found that a different Trem2-KO mouse crossed with a different tau model exacerbated tau pathology (Bemiller et al.”
BackgroundBeyond the neuron–cellular interactions early in Alzheimer disease pathogenesis
Henstridge, C. M., Hyman, B. T., & Spires-Jones, T. L. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0113-1 · Cited by 348 · see citing works
The identity and function of microglia in neurodegeneration
Song, W. M., & Colonna, M. (2018) · Nature Immunology · doi:10.1038/s41590-018-0212-1 · Cited by 308 · see citing works
Self-citationMicroglial phagocytosis of neurons in neurodegeneration, and its regulation
Butler, C. A., Popescu, A. S., Kitchener, E. J. A., Allendorf, D. H., Puigdellívol, M., & Brown, G. C. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15327 · Cited by 293 · see citing works
“Variants of the phagocytic receptor TREM2 are also linked to AD risk, and in a tau mouse model, TREM2 knock- out prevented neuronal loss (Leyns et al., 2017), which is compatible with the idea that neuronal loss may be because of TREM2- mediated phagocytosis.”
BackgroundEmerging roles of innate and adaptive immunity in Alzheimer’s disease
Chen, X., & Holtzman, D. M. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.016 · Cited by 297 · see citing works
Self-citationSengupta, U., & Kayed, R. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102270 · Cited by 303 · see citing works
“Additionally, TREM2 deficiency or TREM2R47H expression provided protection from tau-driven neurodegeneration with attenuated neuroinflammation in PS19 tauopathy mice expressing human mutant tau P301S (Gratuze et al., 2020; Leyns et al., 2017).”
BackgroundNeuroinflammation in frontotemporal dementia
Bright, F., Werry, E. L., Dobson-Stone, C., Piguet, O., Ittner, L. M., Halliday, G. M., Hodges, J. R., Kiernan, M. C., Loy, C. T., Kassiou, M., et al. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0231-z · Cited by 280 · see citing works
Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology
Lee, S.-H., Meilandt, W. J., Xie, L., Gandham, V. D., Ngu, H., Barck, K. H., Rezzonico, M. G., Imperio, J., Lalehzadeh, G., Huntley, M. A., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.02.010 · Cited by 300 · see citing works
Fernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278 · see citing works
The <i>MS4A</i> gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk
Deming, Y., Filipello, F., Cignarella, F., Cantoni, C., Hsu, S., Mikesell, R., Li, Z., Del-Aguila, J. L., Dube, U., Farias, F. G., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aau2291 · Cited by 271 · see citing works
The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders
Carmona, S., Zahs, K., Wu, E., Dakin, K., Bras, J., & Guerreiro, R. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30232-1 · Cited by 244 · see citing works
Impact of TREM2R47H variant on tau pathology–induced gliosis and neurodegeneration
Gratuze, M., Leyns, C. E. G., Sauerbeck, A. D., St-Pierre, M.-K., Xiong, M., Kim, N., Serrano, J. R., Tremblay, M.-È., Kummer, T. T., Colonna, M., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci138179 · Cited by 252 · see citing works
“Previously, we reported a decrease in brain atrophy as well as attenuated microgliosis in the brains of PS19 mice lacking TREM2 without a significant change in tau pathology (25).”
BackgroundResultInfluentialSelf-citationMicroglia in Brain Development, Homeostasis, and Neurodegeneration
Bohlen, C. J., Friedman, B. A., Dejanovic, B., & Sheng, M. (2019) · Annual Review of Genetics · doi:10.1146/annurev-genet-112618-043515 · Cited by 212 · see citing works
The Role of Microglia and the Nlrp3 Inflammasome in Alzheimer's Disease
Hanslik, K. L., & Ulland, T. K. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.570711 · Cited by 236 · see citing works
“Conversely, Trem2 expression in response to tau has been shown to enhance AD-like pathology (30, 31).”
BackgroundMicroglia-neuron crosstalk: Signaling mechanism and control of synaptic transmission
Marinelli, S., Basilico, B., Marrone, M. C., & Ragozzino, D. (2019) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2019.05.017 · Cited by 233 · see citing works
Sayed, F. A., Telpoukhovskaia, M., Kodama, L., Li, Y., Zhou, Y., Le, D., Hauduc, A., Ludwig, C., Gao, F., Clelland, C., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811411115 · Cited by 229 · see citing works
“This result is in agreement with a previous report that showed that complete TREM2 deficiency protected against brain atrophy in P301S mice (22).”
BackgroundResultInfluentialEmerging Microglia Biology Defines Novel Therapeutic Approaches for Alzheimer’s Disease
Lewcock, J. W., Schlepckow, K., Di Paolo, G., Tahirovic, S., Monroe, K. M., & Haass, C. (2020) · Neuron · doi:10.1016/j.neuron.2020.09.029 · Cited by 221 · see citing works
Microglia Gone Rogue: Impacts on Psychiatric Disorders across the Lifespan
Tay, T. L., Béchade, C., D’Andrea, I., St‐Pierre, M., Henry, M. S., Roumier, A., & Tremblay, M. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00421 · Cited by 211 · see citing works
“Genetic deletion of Trem2 in a mouse model of Tau pathology (PS19) resulted in an attenuated atrophy of the entorhinal and piriform cortices, together with increased protein levels of PSD95 in hippocampus (Leyns et al., 2017).”
BackgroundIntersection of pathological tau and microglia at the synapse
Vogels, T., Murgoci, A.-N., & Hromádka, T. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0754-y · Cited by 197 · see citing works
Microglial Phagocytosis: A Disease-Associated Process Emerging from Alzheimer’s Disease Genetics
Podleśny-Drabiniok, A., Marcora, E., & Goate, A. M. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.10.002 · Cited by 211 · see citing works
TREM2, microglia, and Alzheimer’s disease.
Qin, Q., Teng, Z., Liu, C., Li, Q., Yin, Y., & Tang, Y. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111438 · Cited by 219 · see citing works
Transcriptional and epigenetic decoding of the microglial aging process
Li, X., Li, Y., Jin, Y., Zhang, Y., Wu, J., Xu, Z., Huang, Y., Cai, L., Gao, S., Liu, T., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00479-x · Cited by 225 · see citing works
“In contrast, the loss of TREM2 exerts both beneficial and detrimental effects in diverse contexts of tauopathy 36–40 .”
Meilandt, W. J., Ngu, H., Gogineni, A., Lalehzadeh, G., Lee, S.-H., Srinivasan, K., Imperio, J., Wu, T., Weber, M., Kruse, A. J., et al. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.1871-19.2019 · Cited by 210 · see citing works
“, 2007), Trem2 deletion had a protective effect, preventing tau-driven synaptic loss and atrophy in the hippocampus and entorhinal cortex, respectively (Leyns et al., 2017).”
BackgroundResultInflammation context in Alzheimer’s disease, a relationship intricate to define
Novoa, C., Salazar, P., Cisternas, P., Gherardelli, C., Vera-Salazar, R., Zolezzi, J. M., & Inestrosa, N. C. (2022) · Biological Research · doi:10.1186/s40659-022-00404-3 · Cited by 206 · see citing works
The role of innate immune genes in Alzheimer's disease
Griciuc, A., & Tanzi, R. E. (2021) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000911 · Cited by 191 · see citing works
“In a tauopathy mouse model, TREM2 knock-out decreased proinflammatory microglial activation and improved neurodegeneration [98].”
BackgroundTREM2 dependent and independent functions of microglia in Alzheimer’s disease
Hou, J., Chen, Y., Grajales-Reyes, G., & Colonna, M. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00588-y · Cited by 191 · see citing works
Self-citationUpdates on mouse models of Alzheimer’s disease
Zhong, M. Z., Peng, T., Duarte, M. L., Wang, M., & Cai, D. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00712-0 · Cited by 189 · see citing works
Microglia as Dynamic Cellular Mediators of Brain Function
Wright-Jin, E. C., & Gutmann, D. H. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.08.013 · Cited by 186 · see citing works
Mitochondrial Dysfunction and Alzheimer’s Disease: Role of Microglia
Agrawal, I., & Jha, S. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00252 · Cited by 181 · see citing works
Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease
Williams, T., Borchelt, D., & Chakrabarty, P. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-0358-9 · Cited by 166 · see citing works
“This report did not specifically look at Trem2 though another previous report had ahown that attenuating microglial Trem2 is protective against tau-mediated neurodegeneration [213].”
BackgroundXiang, X., Piers, T. M., Wefers, B., Zhu, K., Mallach, A., Brunner, B., Kleinberger, G., Song, W., Colonna, M., Herms, J., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0280-6 · Cited by 170 · see citing works
“For tauopathies there are, however, opposing results indicating either protective or detrimental functions [19, 20].”
ResultSelf-citationZhong, L., Sheng, X., Wang, W., Li, Y., Zhuo, R., Wang, K., Zhang, L., Hu, D.-D., Hong, Y., Chen, L., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.06.016 · Cited by 168 · see citing works
Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice
Kiani Shabestari, S., Morabito, S., Danhash, E. P., McQuade, A., Sanchez, J. R., Miyoshi, E., Chadarevian, J. P., Claes, C., Coburn, M. A., Hasselmann, J., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110961 · Cited by 167 · see citing works
“Recent studies have carefully examined the impact of AD-associated microglial risk genes on A β plaque and neurofibrillary tangle pathologies (Lee et al., 2021; Leyns et al., 2017; Parhizkar et al., 2019, 2019, 2019).”
Limorenko, G., & Lashuel, H. A. (2021) · Chemical Society Reviews · doi:10.1039/d1cs00127b · Cited by 162 · see citing works
Sayed, F. A., Kodama, L., Fan, L., Carling, G. K., Udeochu, J. C., Le, D., Li, Q., Zhou, L., Wong, M. Y., Horowitz, R., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abe3947 · Cited by 155 · see citing works
Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia
Eshraghi, M., Adlimoghaddam, A., Mahmoodzadeh, A., Sharifzad, F., Yasavoli-Sharahi, H., Lorzadeh, S., Albensi, B. C., & Ghavami, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073330 · Cited by 158 · see citing works
“Earlier studies suggested that loss of TREM2 function mitigates neuroinflammation, which protects brain atrophy in the context of tauopathy [247].”
BackgroundChronic TREM2 activation exacerbates Aβ-associated tau seeding and spreading
Jain, N., Lewis, C. A., Ulrich, J. D., & Holtzman, D. M. (2023) · Journal of Experimental Medicine · doi:10.1084/jem.20220654 · Cited by 146 · see citing works
“There is also evidence that once significant tau pathology is in the brain that results in neurodegeneration, as in models of pure tauopathy, loss of TREM2 decreases tau-mediated neurodegeneration (Leyns et al., 2017; Gratuze et al., 2020).”
BackgroundSelf-citationTau-mediated synaptic and neuronal dysfunction in neurodegenerative disease
Tracy, T. E., & Gan, L. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2018.04.027 · Cited by 147 · see citing works
Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets
Nizami, S., Hall‐Roberts, H., Warrier, S., Cowley, S. A., & Di Daniel, E. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14618 · Cited by 147 · see citing works
“TREM2 KO‐hTau mice were shown by one group to have increased pathology and neurodegeneration (Bemiller et al., 2017), while another group reported decreased neuroinflammation and decreased neurodegeneration in the PS19 Tau protein transgenic mouse model (Leyns et al., 2017).”
BackgroundMicroglial priming of antigen presentation and adaptive stimulation in Alzheimer’s disease
Das, R., & Chinnathambi, S. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03132-2 · Cited by 147 · see citing works
Zhao, P., Xu, Y., Jiang, L., Fan, X., Li, L., Li, X., Arase, H., Zhao, Y., Cao, W., Zheng, H., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abq0095 · Cited by 141 · see citing works
“TREM2 deficiency in PS19 mice showed attenuated neuroinflammation and protection against neurodegeneration (70).”
BackgroundResultEwers, M., Biechele, G., Suárez‐Calvet, M., Sacher, C., Blume, T., Morenas‐Rodriguez, E., Deming, Y., Piccio, L., Cruchaga, C., Kleinberger, G., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.202012308 · Cited by 133 · see citing works
“Furthermore, we focus mainly on Ab whereas the evidence for sTREM2 effects on pathologic tau remains preliminary and may be differentially affected by microglia activation (Bemiller et al, 2017; Leyns et al, 2017; Jiang et al, 2018).”
BackgroundAlzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy
Clayton, K. A., Enoo, A. A. V., & Ikezu, T. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00680 · Cited by 132 · see citing works
“However, in a study investigating PS19 mice with TREM2 KO, researchers found a reduction in brain atrophy in the absence of any changes in tauopathy or a reduction of MGnD-associated markers APOE and Cst7 (Krasemann et al., 2017; Leyns et al., 2017).”
BackgroundNew Insights Into Drug Discovery Targeting Tau Protein
Soeda, Y., & Takashima, A. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.590896 · Cited by 133 · see citing works
Shi, Y., Andhey, P. S., Ising, C., Wang, K., Snipes, L. L., Boyer, K., Lawson, S., Yamada, K., Qin, W., Manis, M., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.05.034 · Cited by 135 · see citing works
Self-citationFang, K., Li, H., Chen, X.-X., Gao, X., Huang, L.-L., Du, A.-Q., Jiang, C., Li, H., & Ge, J. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01544 · Cited by 136 · see citing works
Long, H., Simmons, A., Mayorga, A. J., Burgess, B., Nguyen, T., Budda, B., Rychkova, A., Rhinn, H., Tassi, I., Ward, M. E., et al. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01599-1 · Cited by 143 · see citing works
Cholinergic Modulation of Glial Function During Aging and Chronic Neuroinflammation
Gamage, R. V., Wagnon, I. M., Rossetti, I., Childs, R., Niedermayer, G., Chesworth, R., & Gyengési, E. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.577912 · Cited by 133 · see citing works
“This process may be neuroprotective during the earliest stages of amyloid pathology, but with the subsequent occurrence of tau pathology associated with a larger increase in CSF sTREM2, may reflect the transition of microglia to a detrimental phenotype (Leyns et al., 2017; Schmitz et al., 2020).”
BackgroundAntignano, I., Liu, Y., Offermann, N., & Capasso, M. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04775-y · Cited by 117 · see citing works
Cheng, Q., Danao, J., Talreja, S., Wen, P. H., Yin, J., Sun, N., Li, C.-M., Chui, D., Tran, D. T., Koirala, S., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.001848 · Cited by 129 · see citing works
“In fact, recent data pointing to opposing roles for TREM2 in tauopathy can potentially be attributed to the age of the animals and the different genetic models of tauopathy utilized in the two studies and further support the complex nature of TREM2-mediated modulation of neuroinflammation (15, 16).”
BackgroundResultTransgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis
Sanchez-Varo, R. M., Mejias‐Ortega, M., Fernandez-Valenzuela, J. J., Nuñez‐Diaz, C., Cáceres-Palomo, L., Vegas‐Gomez, L., Sánchez‐Mejías, E., Trujillo‐Estrada, L., García‐León, J. A., Moreno‐González, I., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105404 · Cited by 130 · see citing works
“Consequently, these alterations may impact the ability of microglia to compact and phagocyte plaques and, hence, induce local toxicity with DNs formation and the infiltration of peripheral immune cells into the brain [69].”
BackgroundResultMicroglial phagocytosis in aging and Alzheimer's disease
Gabandé‐Rodríguez, E., Keane, L., & Capasso, M. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24419 · Cited by 127 · see citing works
“Finally, it has been suggested that TREM‐2 could also have a role in phagoptosis, by favoring the phagocytosis of stressed viable neurons in a tauopathy mouse model (Leyns et al., 2017).”
BackgroundResultTREM2: Potential therapeutic targeting of microglia for Alzheimer's disease
Li, Y., Xu, H., Wang, H., Yang, K., Luan, J., & Wang, S. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115218 · Cited by 128 · see citing works
Treatment of a genetic brain disease by CNS-wide microglia replacement
Shibuya, Y., Kumar, K. K., Mader, M. M.-D., Yoo, Y., Ayala, L. A., Zhou, M., Mohr, M. A., Neumayer, G., Kumar, I., Yamamoto, R., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abl9945 · Cited by 121 · see citing works
Majdi, A., Sadigh‐Eteghad, S., Aghsan, S. R., Farajdokht, F., Vatandoust, S. M., Abbas-Abad, A. N., & Mahmoudi, J. (2020) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0089 · Cited by 124 · see citing works
Microglia in Alzheimer’s Disease in the Context of Tau Pathology
Perea, J. R., Bolós, M., & Ávila, J. (2020) · Biomolecules · doi:10.3390/biom10101439 · Cited by 127 · see citing works
“Subsequently, another study postulated that lack of TREM2 attenuates neuroinflammation and prevents neuronal death in the P301S mouse [211].”
BackgroundLeveraging preclinical models for the development of Alzheimer disease therapeutics
Scearce-Levie, K., Sanchez, P. E., & Lewcock, J. W. (2020) · Nature reviews. Drug discovery · doi:10.1038/s41573-020-0065-9 · Cited by 100 · see citing works
Dong, Y., Yu, H., Li, X., Bian, K., Zheng, Y., Dai, M., Feng, X., Sun, Y., He, Y. T., Yu, B., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02567-y · Cited by 119 · see citing works
“In the TauP301S tauopathy mouse model, microglial inactivation attenuates neuroinflammation and tau-mediated neurodegeneration, indicating that microglia contribute to neuronal death in models of tau-mediated neurodegeneration [22, 23].”
BackgroundProkop, S., Miller, K. R., Labra, S. R., Pitkin, R. M., Hoxha, K., Narasimhan, S., Changolkar, L., Rosenbloom, A., Lee, V. M.-Y., & Trojanowski, J. Q. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02048-2 · Cited by 119 · see citing works
Schlepckow, K., Morenas‐Rodríguez, E., Hong, S. Y., & Haass, C. (2023) · The Lancet Neurology · doi:10.1016/s1474-4422(23)00247-8 · Cited by 121 · see citing works
Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research
Jung, E. S., Choi, H., & Mook-Jung, I. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00825-0 · Cited by 124 · see citing works
Single-nucleus transcriptomic landscape of primate hippocampal aging
Zhang, H., Li, J., Ren, J., Sun, S., Ma, S., Zhang, W., Yu, Y., Cai, Y., Yan, K., Li, W., et al. (2021) · Protein & Cell · doi:10.1007/s13238-021-00852-9 · Cited by 118 · see citing works
“Among them, TREM2 encodes an essential microglia sensor that mediates their response to environmental signals (Leyns et al., 2017), and its upregulation in microglia is closely related to inflammatory responses and pathogenesis of AD (Keren-Shaul et al., 2017; Ulland and Colonna, 2018).”
BackgroundTREM2 ectodomain and its soluble form in Alzheimer’s disease
Yang, J., Fu, Z., Zhang, X., Xiong, M., Meng, L., & Zhang, Z. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01878-2 · Cited by 113 · see citing works
The informed road map to prevention of Alzheimer Disease: a call to arms
McDade, E., Llibre-Guerra, J. J., Holtzman, D. M., Morris, J. C., & Bateman, R. J. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00467-y · Cited by 89 · see citing works
“While these studies support augmenting TREM function in the amyloid stage of preclinical AD, other studies show that decreasing TREM2 function in tauopathy models decreases brain atrophy and synaptic loss [123, 124].”
BackgroundSelf-citationElevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia
Zhao, N., Qiao, W., Li, F., Ren, Y., Zheng, J., Martens, Y. A., Wang, X., Li, L., Liu, C., Chen, K., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20212479 · Cited by 111 · see citing works
“…studies on TREM2 function in AD using Trem2-knockout mice have generated inconsistent findings of either reducing or enhancing amyloid or tau pathologies (Bemiller et al., 2017; Fitz et al., 2020; Jay et al., 2017; Lee et al., 2021; Leyns et al., 2017; Parhizkar et al., 2019; Yuan et al., 2016).”
BackgroundA cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer’s disease
Yoo, Y., Neumayer, G., Shibuya, Y., Mader, M. M.-D., & Wernig, M. (2023) · Cell Stem Cell · doi:10.1016/j.stem.2023.07.006 · Cited by 109 · see citing works
Distinct Signaling Pathways Regulate TREM2 Phagocytic and NFκB Antagonistic Activities
Yao, H., Coppola, K., Schweig, J. E., Crawford, F., Mullan, M., & Paris, D. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00457 · Cited by 110 · see citing works
“, 2017) or on the opposite prevents the neurodegeneration induced by the tauopathy (Leyns et al., 2017).”
Background
- Authors
- Leyns, C. E. G., Ulrich, J. D., Finn, M. B., Stewart, F. R., Koscal, L. J., Remolina Serrano, J., Robinson, G. O., Anderson, E., Colonna, M., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110;
- Corresponding author
- Holtzman, David M.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-10-09
- Volume
- 114
- Issue
- 43
- Pages
- 11524-11529
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5663386
- OpenAlex
- W2763928642
- Cited by
- 517
- References
- 50
- Citations by year
- 2026: 41 · 2025: 51 · 2024: 55 · 2023: 78 · 2022: 79 · 2021: 69 · 2020: 54 · 2019: 44 · 2018: 42 · 2017: 3 · 2012: 1
- FWCI
- 19.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
- Funders
- Cure Alzheimer's Fund
- Hope Center for Neurological Disorders
- Center for Cellular Imaging, Washington University
- National Institute on Aging (F31AG053976)
- 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
- TREM2, tauopathy, neuroinflammation, neurodegeneration, Alzheimer's disease, microglia, tau pathology, brain atrophy, amyloid-beta, TREM2 deficiency, mouse model
- MeSH terms
- Animals, Gene Expression Regulation, Inflammation, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Mice, Knockout, Neurodegenerative Diseases, Tauopathies, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
