Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Open accessAbstract
Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late-onset Alzheimer's disease (AD). We demonstrate that amyloid plaque seeding is increased in the absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque-associated apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque-associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss-of-function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2, early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque-associated ApoE.
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Numerous studies targeting members of the TREM2/TYROBP pathway (Trem2, Tyrobp, and miR155) support beneficial outcomes associated with maintenance and/or restoration of homeostatic functions of microglia.
“Support for beneficial outcomes associated with maintenance and/or restoration of homeostatic functions of microglia comes from the numerous studies targeting the members of this pathway, including Trem2,48,50–52 Tyrobp,53,54 and miR155.41,55”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [51]
The Discussion (page unavailable) says functional TREM2 may protect against early amyloid seeding by enabling microglia to cluster around and clear newly seeded plaques. But it also says TREM2 loss leaves microglia locked in a homeostatic state while reducing plaque clearance. The paper therefore supports a potential benefit of TREM2 function, not a benefit specifically from maintaining or restoring microglial homeostasis. (LLM, conf=0.86)
Experimental — accuracy not yet measuredConflicting results have been reported regarding amyloid plaque deposition and the effect of TREM2 loss, suggesting that the effect of TREM2 on Ab deposition may be dependent on age, sex, and the model utilized.
“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 [10]
The Results section (“Loss of Trem2 function changes the kinetics of amyloidogenesis”; page unavailable) explicitly says earlier studies reported conflicting plaque-burden results and finds that the effect of Trem2 loss changes with age. The Online Methods (“Transgenic mice”; page unavailable) notes sex-related variability in plaque deposition, but the paper does not show that sex changes the effect of Trem2 loss. It uses two loss-of-function models without establishing that the effect depends on the model. (LLM, conf=0.87)
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 [58]
The Results section (‘Increased amyloid plaque seeding in the absence of functional Trem2’; page unavailable) reports increased amyloidogenesis when Trem2 function is lost. The paper does not establish an opposing effect on tau pathology or effects of manipulating Tyrobp, Cx3cl1/Cx3cr1, IL1β, or IFN-γ, so it supports only the Trem2–amyloid portion of the attributed claim. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe 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 [58]
The Results section, “Increased amyloid plaque seeding in the absence of functional Trem2” (page unavailable), reports increased amyloidogenesis in a second TREM2 loss-of-function model, supporting the TREM2–amyloid part of the claim. This paper does not demonstrate the claimed contrast between immune effects on amyloid and tau, or report a TYROBP model. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn studies of Trem2 deficiency, differences were dependent on early versus later disease stages.
“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 <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [51]
Loss of Trem2 in an APP/PS1 Alzheimer's disease mouse model accelerated amyloidogenesis in early disease pathogenesis, whereas Trem2 deficiency did not affect amyloid load at a later disease stage.
“Loss of Trem2 in an APP/PS1 AD mouse model accelerated amyloidogenesis in early disease pathogenesis, whereas Trem2 deficiency did not affect amyloid load at a later disease stage [37].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [37]
ApoE protein levels are greatly increased in plaque-associated microglia in amyloid mice.
“apoE protein levels are greatly increased in plaque-associated microglia in amyloid mice”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Parhizkar et al 2019
Loss of TREM2 function impairs Aβ phagocytosis by microglia and increases amyloid seeding in AD mouse models.
“Loss of TREM2 function impaired Aβ phagocytosis by microglia and increased amyloid seeding in AD mouse models.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [170]
Microglial functions involved in the initial formation of plaques are related to TREM2 signaling.
“In addition, we show that microglia are necessary for the development of plaques - these findings are supported by recent data showing that plaque seeding is accelerated in Trem2 knockout mice30, suggesting that microglial functions involved in the initial formation of plaques are related to TREM2 signaling.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [30]
Microglia surrounding plaques are a major source of plaque-associated ApoE.
“Thus, microglia surrounding plaques are a major source of plaque-associated ApoE, supporting recent findings30,31.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [30]
Plaque-associated microglia are a source of ApoE.
“Colocalization with the microglia/myeloid marker IBA1 revealed that these ApoE positive processes were indeed microglia (Fig. 6l), confirming that plaque-associated microglia are a source of ApoE30.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [30]
Previous reports describe the coaggregation of ApoE with Aβ fibrils in both plaques and vascular pathology.
“Focusing on plaque structure, we next evaluated the presence of ApoE within plaque cores – previous reports describe the coaggregation of ApoE with Aβ fibrils in both plaques and vascular pathology29,30.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [30]
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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-citationMicroglia 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
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425 · see citing works
APOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches
Serrano-Pozo, A., Das, S., & Hyman, B. T. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30412-9 · Cited by 1,037 · see citing works
Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease
Chen, W.-T., Lu, A., Craessaerts, K., Pavie, B., Sala Frigerio, C., Corthout, N., Qian, X., Laláková, J., Kühnemund, M., Voytyuk, I., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.038 · Cited by 949 · see citing works
Johnson, E. C. B., Dammer, E. B., Duong, D. M., Ping, L., Zhou, M., Yin, L., Higginbotham, L. A., Guajardo, A., White, B., Troncoso, J. C., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0815-6 · Cited by 1,001 · see citing works
Spangenberg, E., Severson, P. L., Hohsfield, L. A., Crapser, J., Zhang, J., Burton, E. A., Zhang, Y., Spevak, W., Lin, J., Phan, N. Y., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11674-z · Cited by 939 · see citing works
TREM2 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
Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease
Mulder, K., Patel, A. A., Kong, W. T., Piot, C., Halitzki, E., Dunsmore, G., Khalilnezhad, S., Irac, S. E., Dubuisson, A., Chevrier, M., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.07.007 · Cited by 678 · see citing works
Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease
Depp, C., Sun, T., Sasmita, A. O., Spieth, L., Berghoff, S. A., Nazarenko, T., Overhoff, K., Steixner-Kumar, A. A., Subramanian, S., Arinrad, S., et al. (2023) · Nature · doi:10.1038/s41586-023-06120-6 · Cited by 476 · see citing works
Self-citationColonna, M. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00837-1 · Cited by 394 · 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
Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition
Colombo, A. V., Sadler, R. K., Llovera, G., Singh, V., Roth, S., Heindl, S., Sebastian Monasor, L., Verhoeven, A., Peters, F., Parhizkar, S., et al. (2021) · eLife · doi:10.7554/elife.59826 · Cited by 354 · see citing works
Self-citationEwers, 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
Self-citationImmune 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
Microglia Phenotypes in Aging and Neurodegenerative Diseases
Wendimu, M. Y., & Hooks, S. B. (2022) · Cells · doi:10.3390/cells11132091 · Cited by 336 · see citing works
Wang, C., Xiong, M., Gratuze, M., Bao, X., Shi, Y., Andhey, P. S., Manis, M., Schroeder, C., Yin, Z., Madore, C., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.03.024 · Cited by 334 · see citing works
Self-citationAstrocytic interleukin-3 programs microglia and limits Alzheimer’s disease
McAlpine, C. S., Park, J., Griciuc, A., Kim, E., Choi, S. H., Iwamoto, Y., Kiss, M. G., Christie, K. A., Vinegoni, C., Poller, W. C., et al. (2021) · Nature · doi:10.1038/s41586-021-03734-6 · Cited by 322 · see citing works
Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region
Schlepckow, K., Monroe, K. M., Kleinberger, G., Cantuti‐Castelvetri, L., Parhizkar, S., Xia, D., Willem, M., Werner, G., Pettkus, N., Brunner, B., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.201911227 · Cited by 324 · see citing works
Self-citationEmerging 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-citationTrem2 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
Microglia 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
Microglia and Astrocytes in Disease: Dynamic Duo or Partners in Crime?
Liddelow, S. A., Marsh, S. E., & Stevens, B. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.07.006 · Cited by 226 · see citing works
Microglia contribute to the propagation of Aβ into unaffected brain tissue
d’Errico, P., Ziegler-Waldkirch, S., Aires, V., Hoffmann, P., Mezö, C., Erny, D., Monasor, L. S., Liebscher, S., Ravi, V. M., Joseph, K., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-021-00951-0 · Cited by 214 · see citing works
Self-citationActivated microglia mitigate Aβ-associated tau seeding and spreading
Gratuze, M., Chen, Y., Parhizkar, S., Jain, N., Strickland, M. R., Serrano, J. R., Colonna, M., Ulrich, J. D., & Holtzman, D. M. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20210542 · Cited by 215 · see citing works
Self-citationLiu, W., Taso, O., Wang, R., Bayram, S., Graham, A. C., Garcia-Reitboeck, P., Mallach, A., Andrews, W. D., Piers, T. M., Botia, J. A., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa209 · Cited by 214 · see citing works
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“Parhizkar et al. (2019) also reported that colocalization of ApoE with Iba1 microglia was reduced in Trem2-deficient mice.”
BackgroundMethodResultInfluentialXCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis
Deczkowska, A., David, E., Ramadori, P., Pfister, D., Safran, M., Li, B., Giladi, A., Jaitin, D. A., Barboy, O., Cohen, M., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01344-3 · Cited by 197 · see citing works
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TREM2 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
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Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice
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Haass, C., & Selkoe, D. (2022) · PLOS Biology · doi:10.1371/journal.pbio.3001694 · Cited by 145 · see citing works
Self-citationEwers, 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
Self-citationMahan, T. E., Wang, C., Bao, X., Choudhury, A., Ulrich, J. D., & Holtzman, D. M. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00516-0 · Cited by 134 · see citing works
Self-citationHuynh, T.-P. V., Wang, C., Tran, A. C., Tabor, G. T., Mahan, T. E., Francis, C. M., Finn, M. B., Spellman, R., Manis, M., Tanzi, R. E., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0337-1 · Cited by 139 · see citing works
Self-citationMargeta, M. A., Yin, Z., Madore, C., Pitts, K. M., Letcher, S. M., Tang, J., Jiang, S., Gauthier, C. D., Silveira, S. R., Schroeder, C. M., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.07.014 · Cited by 130 · see citing works
Self-citationYin, Z., Herron, S., Silveira, S., Kleemann, K., Gauthier, C., Mallah, D., Cheng, Y., Margeta, M. A., Pitts, K. M., Barry, J.-L., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01355-y · Cited by 120 · see citing works
Self-citationProkop, 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
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Magusali, N., Graham, A. C., Piers, T. M., Panichnantakul, P., Yaman, U., Shoai, M., Reynolds, R. H., Botia, J. A., Brookes, K. J., Guetta-Baranes, T., et al. (2021) · Brain · doi:10.1093/brain/awab337 · Cited by 111 · see citing works
APOE genotype and sex affect microglial interactions with plaques in Alzheimer’s disease mice
Stephen, T. L., Cacciottolo, M., Balu, D., Morgan, T. E., LaDu, M. J., Finch, C. E., & Pike, C. J. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0729-z · Cited by 115 · 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
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Self-citationMicroglia and Astrocytes in Alzheimer’s Disease: Significance and Summary of Recent Advances
Deng, Q., Wu, C., Parker, E., Liu, T. C.-Y., Duan, R., & Yang, L. (2023) · Aging and disease · doi:10.14336/ad.2023.0907 · Cited by 102 · see citing works
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Self-citationTerzioglu, G., & Young-Pearse, T. L. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00674-9 · Cited by 95 · see citing works
Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults
Yang, H., Zhang, C., Carlyle, B. C., Zhen, S. Y., Trombetta, B. A., Schultz, A. P., Pruzin, J. J., Fitzpatrick, C. D., Yau, W. W., Kirn, D. R., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12399 · Cited by 90 · see citing works
Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair
De Ponti, F. F., Bujko, A., Liu, Z., Collins, P. J., Schuermans, S., Maueroder, C., Amstelveen, S., Thoné, T., Martens, L., McKendrick, J. G., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.01.002 · Cited by 94 · see citing works
Litvinchuk, A., Huynh, T. V., Shi, Y., Jackson, R. J., Finn, M. B., Manis, M., Francis, C. M., Tran, A. C., Sullivan, P. M., Ulrich, J. D., et al. (2021) · Annals of Neurology · doi:10.1002/ana.26043 · Cited by 91 · see citing works
Self-citationStern, A. M., Yang, Y., Jin, S., Yamashita, K., Meunier, A. L., Liu, W., Cai, Y., Ericsson, M., Liu, L., Goedert, M., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.04.007 · Cited by 91 · see citing works
Shifting paradigms: The central role of microglia in Alzheimer’s disease
Schwabe, T., Srinivasan, K., & Rhinn, H. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104962 · Cited by 84 · see citing works
The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions
Takalo, M., Wittrahm, R., Wefers, B., Parhizkar, S., Jokivarsi, K., Kuulasmaa, T., Mäkinen, P., Martiskainen, H., Wurst, W., Xiang, X., et al. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00402-7 · Cited by 83 · see citing works
Self-citationCastranio, E. L., Hasel, P., Haure‐Mirande, J., Ramirez Jimenez, A. V., Hamilton, B. W., Kim, R. D., Glabe, C. G., Wang, M., Zhang, B., Gandy, S., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12821 · Cited by 74 · see citing works
“50,51,57,58 It remains to be determined whether the increased plaque burden and alterations in microglia phagocytosis described herein in PSAPP mice after Inpp5d knockdown also occur in other mouse models of AD (e.g., 5xFAD), or at different stages during the progression of disease pathology.”
Microbiota‐microglia connections in age‐related cognition decline
Zhou, R., Qian, S., Cho, W. C. S., Zhou, J., Jin, C., Zhong, Y., Wang, J., Zhang, X., Xu, Z., Tian, M., et al. (2022) · Aging Cell · doi:10.1111/acel.13599 · Cited by 71 · see citing works
The VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer’s disease pathology
Lau, S.-F., Wu, W., Wong, H. Y., Ouyang, L., Qiao, Y., Xu, J., Lau, J. H.-Y., Wong, C., Jiang, Y., Holtzman, D. M., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00491-1 · Cited by 70 · see citing works
Self-citationTrem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice
Fitz, N. F., Wolfe, C. M., Playso, B. E., Biedrzycki, R. J., Lu, Y., Nam, K. N., Lefterov, I., & Koldamova, R. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00394-4 · Cited by 68 · see citing works
Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection
Brown, M. R., Radford, S. E., & Hewitt, E. W. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.609073 · Cited by 67 · see citing works
In Vivo Assessment of Neuroinflammation in <scp>4‐Repeat</scp> Tauopathies
Palleis, C., Sauerbeck, J., Beyer, L., Harris, S., Schmitt, J., Morenas‐Rodriguez, E., Finze, A., Nitschmann, A., Ruch‐Rubinstein, F., Eckenweber, F., et al. (2021) · Movement Disorders · doi:10.1002/mds.28395 · Cited by 62 · see citing works
Self-citationMicroglial Activation and Connectivity in Alzheimer Disease and Aging
Rauchmann, B., Brendel, M., Franzmeier, N., Trappmann, L., Zaganjori, M., Ersoezlue, E., Morenas‐Rodriguez, E., Guersel, S., Burow, L., Kurz, C., et al. (2022) · Annals of Neurology · doi:10.1002/ana.26465 · Cited by 61 · see citing works
“Limited blood – brain barrier passing of [ 18 F]GE-180 needs to be acknowledged, but our previous data indicated strong agreement with immunohistochemistry in AD models 58 and patterns matching known topology of microglial activation in neurodegenerative diseases.”
ResultSelf-citationPan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis
Pedicone, C., Fernandes, S., Dungan, O. M., Dormann, S. M., Viernes, D. R., Adhikari, A. A., Choi, L. B., De Jong, E. P., Chisholm, J. D., & Kerr, W. G. (2020) · Journal of Cell Science · doi:10.1242/jcs.238030 · Cited by 61 · see citing works
ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
Li, Y., Macyczko, J. R., Liu, C.-C., & Bu, G. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.03.011 · Cited by 61 · see citing works
Larramona-Arcas, R., González-Arias, C., Perea, G., Gutiérrez, A., Vitorica, J., García-Barrera, T., Gómez-Ariza, J. L., Pascua-Maestro, R., Ganfornina, M. D., Kara, E., et al. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00382-8 · Cited by 56 · see citing works
The role of TREM2 in Alzheimer’s disease: from the perspective of Tau
Huang, W., Huang, J., Huang, N., & Luo, Y. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1280257 · Cited by 49 · see citing works
McFarland, K. N., & Chakrabarty, P. (2022) · Neurotherapeutics · doi:10.1007/s13311-021-01179-3 · Cited by 48 · see citing works
Diagnostic biomarkers in Alzheimer’s disease
Andersen, E., Casteigne, B., Chapman, W. D., Creed, A., Foster, F., Lapins, A., Shatz, R., & Sawyer, R. P. (2021) · Biomarkers in Neuropsychiatry · doi:10.1016/j.bionps.2021.100041 · Cited by 42 · see citing works
Henningfield, C. M., Arreola, M. A., Soni, N., Spangenberg, E. E., & Green, K. N. (2022) · Glia · doi:10.1002/glia.24105 · Cited by 40 · see citing works
Feiten, A. F., Dahm, K., Schlepckow, K., van Lengerich, B., Suh, J. H., Reifschneider, A., Wefers, B., Bartos, L. M., Wind-Mark, K., de Weerd, L., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-68706-8 · Cited by 39 · see citing works
Self-citationINPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model
Iguchi, A., Takatori, S., Kimura, S., Muneto, H., Wang, K., Etani, H., Ito, G., Sato, H., Hori, Y., Sasaki, J., et al. (2023) · iScience · doi:10.1016/j.isci.2023.106375 · Cited by 37 · see citing works
He, S., Li, X., Mittra, N., Bhattacharjee, A., Wang, H., Song, S., Zhao, S., Liu, F., & Han, X. (2025) · Advanced Science · doi:10.1002/advs.202410910 · Cited by 34 · see citing works
Vautheny, A., Duwat, C., Aurégan, G., Joséphine, C., Hérard, A.-S., Jan, C., Mitja, J., Gipchtein, P., Gaillard, M.-C., Buée, L., et al. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105398 · Cited by 28 · see citing works
Teipel, S. J., Dyrba, M., Ballarini, T., Brosseron, F., Bruno, D., Buerger, K., Cosma, N.-C., Dechent, P., Dobisch, L., Düzel, E., et al. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-215196 · Cited by 20 · see citing works
TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo
Lee-Gosselin, A., Jury-Garfe, N., You, Y., Dabin, L., Soni, D., Dutta, S., Rochet, J.-C., Kim, J., Oblak, A. L., & Lasagna-Reeves, C. A. (2023) · Cells · doi:10.3390/cells12121597 · Cited by 19 · see citing works
Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways
Ibanez, K. R., McFarland, K. N., Phillips, J., Allen, M., Lessard, C. B., Zobel, L., De La Cruz, E. G., Shah, S., Vo, Q., Wang, X., et al. (2022) · Alzheimer's Research & Therapy · doi:10.1186/s13195-022-01044-1 · Cited by 18 · see citing works
Takalo, M., Jeskanen, H., Rolova, T., Kervinen, I., Hellén, M., Heikkinen, S., Koivisto, H., Jokivarsi, K., Müller, S. A., Koivumäki, E.-M., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03387-6 · Cited by 15 · see citing works
“β-Amyloid plaque-associated APOE has been suggested to increase plaque compaction and support microglial responses toward β-amyloid deposition [48, 49].”
Self-citationApoE expression across the CNS: Who, What, Where, When, and How (much)?
Nolt, G. L., Lucido, C. C., Smith, L. M., & Johnson, L. A. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00028-x · Cited by 2 · see citing works
- Authors
- Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deussing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., Krasemann, S., Lichtenthaler, S. F., Müller, S. A., Colombo, A., Monasor, L. S., Tahirovic, S., Herms, J., Willem, M., Pettkus, N., Butovsky, O., Bartenstein, P., Edbauer, D., Rominger, A., Ertürk, A., Grathwohl, S. A., Neher, J. J., Holtzman, D. M., Meyer-Luehmann, M., & Haass, C.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- German Center for Neurodegenerative Diseases (DE)
- Munich Cluster for Systems Neurology (DE)
- Washington University in St. Louis (US)
- Institut für Schlaganfall- und Demenzforschung (DE)
- University of Freiburg (DE)
- Brigham and Women's Hospital (US)
- University Hospital of Bern (CH)
- Hertie Institute for Clinical Brain Research (DE)
- Corresponding author
- Haass, Christian
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2019-01-07
- Volume
- 22
- Issue
- 2
- Pages
- 191-204
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6417433
- OpenAlex
- W2907318708
- Cited by
- 555
- References
- 60
- Citations by year
- 2026: 50 · 2025: 70 · 2024: 64 · 2023: 82 · 2022: 89 · 2021: 82 · 2020: 80 · 2019: 38
- FWCI
- 34.38
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-08-14)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-16-COEN-0005)
- National Institute on Aging (R01AG047644, R01AG051812, RF1AG047644, R01AG054672)
- National Institute of Neurological Disorders and Stroke (R01NS090934, R01NS088137, RF1NS090934)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, Alzheimer's disease, amyloid seeding, amyloid plaques, apolipoprotein E, microglia, microglial activation, amyloid clearance, amyloidogenesis, phagocytosis, microglia depletion
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Apolipoproteins E, Brain, Disease Models, Animal, Genotype, Humans, Membrane Glycoproteins, Mice, Transgenic, Phagocytosis, Receptors, Immunologic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Mice, Plaque, Amyloid
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