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Cited by 19Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and Treatments

TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo

Open access
Lee-Gosselin, Audrey, Jury-Garfe, Nur, You, Yanwen, Dabin, Luke, Soni, Disha, Dutta, Sayan, Rochet, Jean-Christophe, Kim, Jungsu +2 more·2023·Cells
DOI 10.3390/cells12121597PMC PMC10296847
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Abstract

The role of TREM2 in Alzheimer’s disease (AD) is not fully understood. Previous studies investigating the effect of TREM2 deletion on tauopathy mouse models without the contribution of b-amyloid have focused only on tau overexpression models. Herein, we investigated the effects of TREM2 deficiency on tau spreading using a mouse model in which endogenous tau is seeded to produce AD-like tau features. We found that Trem2−/− mice exhibit attenuated tau pathology in multiple brain regions concomitant with a decreased microglial density. The neuroinflammatory profile in TREM2-deficient mice did not induce an activated inflammatory response to tau pathology. These findings suggest that reduced TREM2 signaling may alter the response of microglia to pathological tau aggregates, impairing their activation and decreasing their capacity to contribute to tau spreading. However, caution should be exercised when targeting TREM2 as a therapeutic entry point for AD until its involvement in tau aggregation and propagation is better understood.

AI snapshot

Written from the paper’s full text.

TL;DR

In a mouse model where endogenous tau is seeded by human AD brain-derived tau aggregates, TREM2 deficiency attenuated tau spreading and reduced microglial density without an activated inflammatory response. The authors conclude that reduced TREM2 signaling may impair microglial contribution to tau propagation, but caution against targeting TREM2 therapeutically until its role in tau aggregation and propagation is clearer.

Key findings

  • Trem2−/− mice showed an overall reduction in AT8-positive tau inclusions; no significant differences were observed on the ipsilateral side, but AT8 staining was significantly reduced in areas attributed to tau propagation, including the mammillary area and contralateral retrosplenial cortex.
  • AD-tau-injected WT mice had increased IBA1-positive microglia in the mammillary area, whereas Trem2−/− AD-tau mice had significantly fewer microglia in the mammillary area, contralateral retrosplenial cortex, and ipsilateral ventral hippocampus, with a trend toward fewer in the ipsilateral retrosplenial cortex (p = 0.066).
  • No statistically significant differences in GFAP-positive astrocyte numbers were found between groups in the examined areas.
  • NanoString analysis of 770 genes and 23 neuroinflammatory pathways showed that Trem2−/− AD-tau mice had lower expression of microglial function, adaptive immune response, inflammatory signaling, and cytokine signaling genes than WT AD-tau mice; Trem2−/− PBS mice also showed a lower neuroinflammatory profile than WT-PBS mice.

Methods

  • Three-month-old C57BL/6J WT and Trem2−/− mice were unilaterally injected with sarkosyl-insoluble tau aggregates isolated from the frontal cortex of an 86-year-old female with AD (Braak stage 6); 5 µg total AD-tau was injected into the dorsal hippocampus and overlying cortex.
  • Brains were analyzed at 9 months of age, six months post-injection, using AT8 immunohistochemistry, IBA1/GFAP immunofluorescence, microscopy image analysis, and NanoString neuroinflammation panel on RNA from the ipsilateral hemisphere.
  • Statistical analyses used unpaired Student’s t tests or two-way ANOVA with Tukey’s correction; n = 4–6 mice per experiment with equal numbers of females and males; DEGs were defined as p < 0.05 and log2 fold change > ±0.58.

Limitations

  • The paper states that further studies are necessary to determine the specific role of astrocytes in tau spreading and possible TREM2 involvement, and that it remains unclear whether effects are due to loss of TREM2 itself as a receptor or to a significant loss of microglial function.
  • The paper cautions that TREM2 should not be targeted therapeutically for AD until its involvement in tau aggregation and propagation is better understood.
  • Evident from the text: tau was extracted from a single human AD brain donor, the transcriptomic analysis was described as partial, and the study did not establish a direct mechanism linking TREM2 deficiency to reduced tau spreading.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/cells12121597

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

64 of 80 cited sources checked · 39 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    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.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [12] Bemiller, 2017, TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy, Mol. Neurodegener. source
    • cites [13] Leyns, 2017, TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy, Proc. Natl. Acad. Sci. USA source
    • cites [15] Vautheny, 2021, THY-Tau22 mouse model accumulates more tauopathy at late stage of the disease in response to microglia deactivation through TREM2 deficiency, Neurobiol. Dis. source
  • Premisecitation

    TREM2 deletion increased the abundance of hyperphosphorylated tau dystrophic neurites surrounding amyloid plaques in mice harboring beta-amyloid pathology injected with human AD tau aggregates.

    “TREM2 deletion increased the abundance of hyperphosphorylated tau dystrophic neurites surrounding amyloid plaques [19].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [19] Leyns, 2019, TREM2 function impedes tau seeding in neuritic plaques, Nat. Neurosci. source
  • Premisecitation

    Microglia can actively phagocytize tau.

    “Multiple studies have demonstrated that microglia can actively phagocytize tau”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [23] Hopp, 2018, The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease, J. Neuroinflamm. source
    • cites [34] Asai, 2015, Depletion of microglia and inhibition of exosome synthesis halt tau propagation, Nat. Neurosci. source
    • cites [35] Bolos, 2016, Direct Evidence of Internalization of Tau by Microglia In Vitro and In Vivo, J. Alzheimer’s Dis. source
    • cites [36] Luo, 2015, Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody, Sci. Rep. source
  • Premisecitation

    Microglia have a preponderant role in the spread of pathological tau throughout the brain.

    “supporting a preponderant role of microglia in the spread of pathological tau throughout the brain [23,34,35,36].”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [23] Hopp, 2018, The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease, J. Neuroinflamm. source

      The Discussion says microglia may play a direct role in propagating tau pathology throughout the brain, and reports that they can release tau seeds. It does not establish that their role is preponderant; the Abstract Conclusions describe their contribution to spreading as potential and their role as complex. No page numbers were supplied for these passages. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [34] Asai, 2015, Depletion of microglia and inhibition of exosome synthesis halt tau propagation, Nat. Neurosci. source

      The Discussion reports that microglia play a significant role in tau propagation, with marked reductions after microglial depletion in two mouse models. The tested spread was in specified brain regions, and the paper also acknowledges other propagation pathways; it does not establish that microglia have a preponderant role throughout the brain. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [35] Bolos, 2016, Direct Evidence of Internalization of Tau by Microglia In Vitro and In Vivo, J. Alzheimer’s Dis. source

      The Abstract reports that microglia internalize tau in vitro and in vivo, and the Discussion proposes that increasing microglial clearance of extracellular tau could help arrest tau pathology. These passages support a role for microglia in handling tau, but do not establish that they have a preponderant role in spreading pathological tau throughout the brain. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [36] Luo, 2015, Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody, Sci. Rep. source

      The Discussion says impaired microglial clearance of tau may allow its accumulation and inter-neuronal spread, so the paper links microglia to spread indirectly. It presents this as a hypothesis requiring in vivo validation, not as evidence that microglia have a preponderant role in spreading pathological tau throughout the brain. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Complete deficiency in TREM2 protected PS19 mice against tau-mediated microgliosis and brain atrophy.

    “a complete deficiency in TREM2 protected PS19 mice against tau-mediated microgliosis and brain atrophy [18].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [18] Sayed, 2018, Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy, Proc. Natl. Acad. Sci. USA source

      In the Results section on atrophy and microgliosis (page unavailable), complete TREM2 deficiency protected P301S mice against hippocampal atrophy. The same section reports only a trend toward reduced microglial density, although it found fewer morphological signs of microglial activation. Thus, saying it protected against microgliosis overstates the density finding. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 35
  • May combine two claims. 27

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Trem2-mediated signaling inhibits the transition of microglia to a Disease-Associated Microglia (DAM) state characterized by enhanced migration, chemotaxis, and phagocytosis.

    “Trem2-mediated signaling is known to inhibit the transition of microglia to a more Disease-Associated Microglia (DAM) state characterized by enhanced migration, chemotaxis, and phagocytosis [44,45].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [44] Spinrad, 2017, A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease, Cell source

      The Discussion states that the transition to fully activated DAM is Trem2-dependent and does not occur without the Trem2 receptor. The Results likewise report that Trem2-knockout AD-model mice lacked fully activated DAM. This is contrary to the claim that Trem2-mediated signaling inhibits the transition; page numbers were not supplied in our copy. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [45] Mazaheri, 2017, TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury, EMBO Rep. source

      The Discussion (page not provided) predicts the opposite: loss of Trem2 may lock microglia in a resting state and prevent activation. The paper also reports that Trem2-deficient microglia respond less to chemotactic stimuli and migrate less toward injured neurons. It does not support the claim that Trem2 signaling inhibits the transition to an activated state. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TREM2 ablation in the hTau model exacerbates tau hyperphosphorylation and aggregation.

    “TREM2 ablation in the hTau model that expresses only human tau isoforms [16] exacerbates tau hyperphosphorylation and aggregation [12].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Bemiller, 2017, TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy, Mol. Neurodegener. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Conflicting 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.”
    Quote in the paperNot a substantial claim4 of 5 sources checked
    • cites [7] Jay, 2015, TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models, J. Exp. Med. source
    • cites [8] Jay, 2017, Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer’s Disease, J. Neurosci. source
    • cites [9] Meilandt, 2020, Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Abeta42:Abeta40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer’s Mouse Model, J. Neurosci. source
    • cites [10] Parhizkar, 2019, Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE, Nat Neurosci. source

      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 measured
    • cites [11] Wang, 2015, TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model, Cell source

      The Introduction contrasts a prior APPPS1–21 finding of no increased Aβ accumulation with this paper’s finding of increased accumulation in 5XFAD mice, supporting differing results across models. The Results suggest that deposition kinetics and age may explain why a cortical difference was not detectable at 8.5 months. Neither passage addresses sex as a possible determinant. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    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.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [12] Bemiller, 2017, TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy, Mol. Neurodegener. source
    • cites [13] Leyns, 2017, TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy, Proc. Natl. Acad. Sci. USA source
    • cites [14] Lee, 2021, Trem2 restrains the enhancement of tau accumulation and neurodegeneration by beta-amyloid pathology, Neuron source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In the PS19 model, a 50% decrease in TREM2 but not a total reduction enhanced tau phosphorylation and aggregation.

    “In another study that evaluated the effect of TREM2 loss-of-function in the PS19 model, a 50% decrease in TREM2 but not a total reduction enhanced tau phosphorylation and aggregation [18].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Sayed, 2018, Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy, Proc. Natl. Acad. Sci. USA source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Coding alterations in TREM2 dramatically increase the risk of developing late-onset Alzheimer's disease (LOAD).

    “Coding alterations in TREM2, a transmembrane glycoprotein expressed on myeloid lineage cells that modulates innate immune function [1], dramatically increase the risk of developing late-onset Alzheimer’s disease (LOAD) [2,3].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [2] Guerreiro, 2013, TREM2 variants in Alzheimer’s disease, N. Engl. J. Med. source
    • cites [3] Jonsson, 2013, Variant of TREM2 associated with the risk of Alzheimer’s disease, N. Engl. J. Med. source

      The Abstract Results report that one coding alteration, rs75932628-T (R47H), is associated with approximately threefold higher odds of Alzheimer’s disease. The Results section says no other TREM2 variant likely to affect protein function showed a nominally significant association, so this paper does not support the broader claim that coding alterations generally increase LOAD risk. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Leyns, 2017, TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy, Proc. Natl. Acad. Sci. USA source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Osgin1 protects astrocytes against oxidative insults.

    “and Osgin1 protects astrocytes against oxidative insults [29].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [29] Brennan, 2017, The NRF2 transcriptional target, OSGIN1, contributes to monomethyl fumarate-mediated cytoprotection in human astrocytes, Sci. Rep. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TREM2 haploinsufficiency (50% reduction in TREM2 levels) increased tau pathology.

    “TREM2 haploinsufficiency (50% reduction in TREM2 levels) increased tau pathology [18].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Sayed, 2018, Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy, Proc. Natl. Acad. Sci. USA source

      The Results section, “TREM2 Haploinsufficiency Exacerbates Tau Pathology in P301S Mice,” reports significantly increased tau-pathology staining in P301S mice with one TREM2 allele compared with mice with two. The passages identify the model as TREM2 haploinsufficiency, but do not establish the parenthetical claim that TREM2 levels were reduced by exactly 50%. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent in vivo studies suggest TREM2 may be protective or damaging depending on the pathological stage.

    “recent in vivo studies suggest that TREM2 may be protective or damaging depending on the pathological stage [19,30,31,32].”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [19] Leyns, 2019, TREM2 function impedes tau seeding in neuritic plaques, Nat. Neurosci. source

      The paper’s Abstract (page not provided) reports that reduced TREM2 function increases tau seeding around amyloid plaques, supporting a protective role for TREM2 in that setting. It does not show that TREM2 is damaging at another pathological stage or establish a stage-dependent switch between protective and damaging effects. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [30] Colonna, 2016, TREM2 variants: New keys to decipher Alzheimer disease pathogenesis, Nat. Rev. Neurosci. source
    • cites [31] Gratuze, 2020, Impact of TREM2R47H variant on tau pathology-induced gliosis and neurodegeneration, J. Clin. Investig. source
    • cites [32] Yuan, 2016, TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy, Neuron source

      The Discussion (page unavailable) describes a potentially neuroprotective TREM2-dependent microglial barrier around amyloid plaques. It does not report that TREM2 becomes damaging at another pathological stage, so it supports the protective possibility but not the proposed stage-dependent reversal. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Microglia could promote tau-seed propagation due to failure to process tau aggregates into a non-toxic form, subsequently releasing tau-seed within exosomes in adjacent cells.

    “microglia could promote tau-seed propagation due to its failure to process tau aggregates into a non-toxic form, subsequently releasing this tau-seed within exosomes in adjacent cells [23].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] Hopp, 2018, The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease, J. Neuroinflamm. source

      The Discussion says microglia can fail to fully process tau and release seed-competent tau into conditioned media, potentially contributing to its spread. It describes release via exosomes as one possibility, not an established mechanism, and does not show release within exosomes into adjacent cells. Page numbers are not provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In PS19 mice crossed with Trem2 KO mice, brain atrophy and microgliosis were reduced.

    “brain atrophy and microgliosis were reduced [13].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Leyns, 2017, TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy, Proc. Natl. Acad. Sci. USA source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Psmb8 and Mmp12 are associated with detrimental roles in the brain.

    “Conversely, the proteasome subunit (Psmb8) and matrix metalloproteinase-12 (Mmp12) are associated with detrimental roles in the brain [25,26].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [25] Orre, 2013, Reactive glia show increased immunoproteasome activity in Alzheimer’s disease, Brain source
    • cites [26] Chelluboina, 2015, Post-transcriptional inactivation of matrix metalloproteinase-12 after focal cerebral ischemia attenuates brain damage, Sci. Rep. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TREM2 ablation significantly increased tau pathology in the hTau mouse model expressing all six isoforms of human tau.

    “TREM2 ablation significantly increased tau pathology in the hTau mouse model expressing all six isoforms of human tau [12].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Bemiller, 2017, TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy, Mol. Neurodegener. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cd109 and B3gnt5 are known markers of neuroprotective astrocytes.

    “Notably, Cd109 and B3gnt5 are known markers of neuroprotective astrocytes [27,28]”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [27] Kisucka, A., Bimbova, K., Bacova, M., Galik, J., and Lukacova, N. (2021). Activation of Neuroprotective Microglia and Astrocytes at the Lesion Site and in the Adjacent Segments Is Crucial for Spontaneous Locomotor Recovery after Spinal Cord Injury. Cells, 10. source

      Results §3.2 identifies CD109 as a marker of neuroprotective A2 astrocytes. Our copy does not identify B3gnt5 as such a marker; a search for B3gnt5 found no relevant passage. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [28] Clarke, 2018, Normal aging induces A1-like astrocyte reactivity, Proc. Natl. Acad. Sci. USA source

      The Results section identifies Emp1 as an A2 astrocyte marker, but does not identify Cd109 or B3gnt5 as markers. Searches for both gene names and neuroprotective astrocyte markers found no passage in our copy establishing the claim. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cytokines released by microglia trigger specific intraneuronal signaling that causes tau seeding and hyperphosphorylation.

    “cytokines released by microglia trigger specific intraneuronal signaling that causes tau seeding and hyperphosphorylation [37,38].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [37] Gorlovoy, 2009, Accumulation of tau induced in neurites by microglial proinflammatory mediators, FASEB J. source
    • cites [38] Maphis, 2015, Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain, Brain source

      The Discussion (page unavailable) suggests that IL1B from activated microglia drives tau pathology and identifies neuronal IL-1R–p38 MAPK signaling. The Results (page unavailable) show microglia-induced tau hyperphosphorylation that is reduced by blocking IL-1 signaling. The paper reports early tau aggregation and possible spread, but does not establish that this cytokine-driven signaling causes tau seeding. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    C3ar1 deletion rescued tau pathology and attenuated neuroinflammation, synaptic deficits, and neurodegeneration in the PS19 tauopathy mouse model.

    “Notably, in a previous study, C3ar1 (C3a receptor) deletion rescued tau pathology and attenuated neuroinflammation, synaptic deficits, and neurodegeneration in the PS19 tauopathy mouse model [24].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Litvinchuk, 2018, Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease, Neuron source

  • May combine two claims.

    Premisecitation

    Microglial depletion and exosome synthesis inhibition reduce tau propagation in vivo.

    “Asai and collaborators demonstrated that microglial depletion and exosome synthesis inhibition reduce tau propagation in vivo [34]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] Asai, 2015, Depletion of microglia and inhibition of exosome synthesis halt tau propagation, Nat. Neurosci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    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”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Leyns, 2017, TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy, Proc. Natl. Acad. Sci. USA source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TREM2-deficient microglia have impaired proliferative ability and decreased viability.

    “TREM2-deficient microglia have also been shown to have an impaired proliferative ability and decreased viability [11,47].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [11] Wang, 2015, TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model, Cell source

      The Results section, “TREM2 deficiency affects microglia survival in 5XFAD mice” (page unavailable), reports reduced viability under low-CSF-1 conditions and more apoptotic microglia in TREM2-deficient 5XFAD mice. It does not establish impaired proliferative ability: under the tested in-vitro conditions, TREM2 deficiency did not affect microglial expansion. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [47] Wang, 2016, TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques, J. Exp. Med. source

      In Results and Discussion, under “TREM2 deficiency affects plaque-associated microglial proliferation” (page unavailable), plaque-associated Ki-67-positive microglia were nearly undetectable in TREM2-deficient 5XFAD mice, supporting impaired proliferation around plaques. The passages do not report decreased microglial viability, so that part of the claim is unsupported by this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    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].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Leyns, 2017, TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy, Proc. Natl. Acad. Sci. USA source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TREM2 can regulate microglia phagocytic activity.

    “compelling evidence suggesting that TREM2 can regulate microglia phagocytic activity [44,45]”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [44] Spinrad, 2017, A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease, Cell source
    • cites [45] Mazaheri, 2017, TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury, EMBO Rep. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TREM2 deletion aggravates tau spreading, possibly through microglial extracellular exosomes.

    “The authors demonstrated that TREM2 deletion aggravates tau spreading, possibly through microglial extracellular exosomes.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [43] Zhu, 2022, Trem2 deletion enhances tau dispersion and pathology through microglia exosomes, Mol. Neurodegener. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    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].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [8] Jay, 2017, Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer’s Disease, J. Neurosci. source
    • cites [13] Leyns, 2017, TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy, Proc. Natl. Acad. Sci. USA source

  • May combine two claims.

    Interpretationcitation

    Loss of TREM2 function impacts microglial activation, hindering inflammatory responses.

    “suggesting that loss of TREM2 function impacts microglial activation, hindering inflammatory responses [13].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Leyns, 2017, TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy, Proc. Natl. Acad. Sci. USA source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Removing microglia inhibited the spread of tau pathology in an amyloid-free setting.

    “removing microglia inhibited the spread of tau pathology in an amyloid-free setting [34]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] Asai, 2015, Depletion of microglia and inhibition of exosome synthesis halt tau propagation, Nat. Neurosci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TREM2 deletion promotes tau trafficking to late endosome/pre-exosomal compartments.

    “they suggested that TREM2 deletion promotes tau trafficking to late endosome/pre-exosomal compartments [43].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [43] Zhu, 2022, Trem2 deletion enhances tau dispersion and pathology through microglia exosomes, Mol. Neurodegener. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TREM2 deletion enhanced tau spreading from the medial entorhinal cortex (MEC) to the hippocampal dentate gyrus (DG) in a model using AAV expression of P301L tau.

    “a recent study using the adeno-associated virus (AAV) expression of P301L tau showed that TREM2 deletion enhanced tau spreading from the medial entorhinal cortex (MEC) to the hippocampal dentate gyrus (DG) [43].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [43] Zhu, 2022, Trem2 deletion enhances tau dispersion and pathology through microglia exosomes, Mol. Neurodegener. source

  • May combine two claims.

    Findingown data

    In AD-tau WT mice, microglial function is enhanced compared with PBS-injected controls, but this enhancement is not seen in AD-tau Trem2−/− mice.

    “the transcriptomic-based analysis demonstrated that microglial function is enhanced in AD-tau WT mice but not in AD-tau Trem2−/− mice in comparison with that in PBS-injected controls”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Differential gene expression analysis revealed changes in genes related to microglia function in Trem2−/− AD-tau mice, whereas Trem2−/− PBS mice exhibited alterations in genes related to both microglial function and inflammatory signaling.

    “Differential gene expression analysis revealed changes in genes related to microglia function in Trem2−/− AD-tau mice, whereas Trem2−/− PBS mice exhibited alterations in genes related to both microglial function and inflammatory signaling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Trem2−/− mice injected with AD-tau showed decreased microglial function and inflammatory signaling in comparison with WT AD-tau mice.

    “Third, Trem2−/− mice injected with AD-tau (Trem2−/− AD-tau) showed decreased microglial function and inflammatory signaling in comparison with WT AD-tau mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Osgin1 and Cd109 were downregulated in Trem2−/− AD-tau versus WT AD-tau mice.

    “While this difference was not significant (Supplementary Figure S3A), the analysis of the individual normalized gene expression levels of astrocyte function-related genes revealed that Osgin1 (Supplementary Figure S3B) and Cd109 (Supplementary Figure S3C) were downregulated in Trem2−/− AD-tau versus WT AD-tau mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The microglial function score was significantly higher in WT AD-tau mice than in WT-PBS mice; no differences were observed in any of the comparisons with Trem2−/− mice.

    “The microglial function score (Figure 6A) was significantly higher in WT AD-tau mice than in WT-PBS mice; however, no differences were observed in any of the comparisons with Trem2−/− mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    C3ar1, Psmb8, and Mmp12 were downregulated in Trem2−/− AD-tau mice versus WT AD-tau mice.

    “However, the individual normalized gene expression levels of three microglial function-related genes revealed that C3ar1 (Figure 6B), Psmb8 (Figure 6C), and Mmp12 (Figure 6D) were downregulated in Trem2−/− AD-tau mice versus WT AD-tau mice.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Equivalent brain sections were selected for every region analyzed, using the injection location identified by Nissl as a reference, to ensure accurate comparisons between experimental conditions.

    “To ensure accurate comparisons between experimental conditions, equivalent brain sections were selected for every region analyzed, using the injection location identified by Nissl as a reference.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    The effect of TREM2 ablation on tau propagation remains unclear.

    “All previous in vivo studies evaluating the effect of TREM2 deletion on tauopathy mouse models without the contribution of b-amyloid have been conducted in tau overexpression models; thus, the effect of TREM2 ablation on tau propagation remains unclear.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Statistical significance levels for comparison models and volcano plot generation were corrected for multiple comparisons using the Benjamini-Hochberg false discovery rate (FDR) method.

    “The statistical significance levels for the comparison models and volcano plot generation were corrected for multiple comparisons using the Benjamini–Hochberg false discovery rate (FDR) method.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Reduced TREM2 signaling may alter the response of microglia to pathological tau aggregates, impairing their activation and decreasing their capacity to contribute to tau spreading.

    “These findings suggest that reduced TREM2 signaling may alter the response of microglia to pathological tau aggregates, impairing their activation and decreasing their capacity to contribute to tau spreading.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Gene expression changes measured in whole ipsilateral hemisphere by NanoString reflect microglial and astrocytic function.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    TREM2 deletion exacerbates tau pathology and promotes brain atrophy in a mouse model overexpressing human tau with P301L and human APP.

    “In a recently published study, TREM2 deletion was found to exacerbate tau pathology and promote brain atrophy in a mouse model that overexpressed human tau with the P301L mutation and human amyloid precursor protein (APP) but had no effect in a model that solely overexpressed mutant tau, suggesting that TREM2 function is neither protective nor detrimental in a pure tauopathy setting [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Lee, 2021, Trem2 restrains the enhancement of tau accumulation and neurodegeneration by beta-amyloid pathology, Neuron source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TREM2 deletion has no effect on tau pathology in a mouse model solely overexpressing mutant tau.

    “In a recently published study, TREM2 deletion was found to exacerbate tau pathology and promote brain atrophy in a mouse model that overexpressed human tau with the P301L mutation and human amyloid precursor protein (APP) but had no effect in a model that solely overexpressed mutant tau, suggesting that TREM2 function is neither protective nor detrimental in a pure tauopathy setting [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Lee, 2021, Trem2 restrains the enhancement of tau accumulation and neurodegeneration by beta-amyloid pathology, Neuron source

  • May combine two claims.

    Interpretationown data

    A lack of TREM2 alters microglial proliferation or survival but not reactivity in response to AD-tau propagation.

    “suggesting that a lack of TREM2 alters microglial proliferation or survival but not reactivity in response to AD-tau propagation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Conflicting results on TREM2 and tau pathology could be due to the different TREM2-deficient mouse models used in each study.

    “These conflicting results could also be due to the different TREM2-deficient mouse models used in each of these studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Microglial function is impacted by Trem2 depletion, with specific genes becoming downregulated in response to AD-tau, while inflammatory signaling is altered primarily due to TREM2−/− deficiency.

    “These findings suggest that microglial function is impacted by Trem2 depletion, with specific genes becoming downregulated in response to AD-tau, while inflammatory signaling is altered primarily due to TREM2−/− deficiency.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Gene expression changes measured in whole ipsilateral hemisphere by NanoString reflect microglial and astrocytic function.

  • May combine two claims.

    Interpretationreasoning

    The effect of TREM2 on tau pathology likely depends on the overall expression levels of TREM2 and the stage and type of pathology, which is model-dependent.

    “the effect of TREM2 on tau pathology likely depends on the overall expression levels of TREM2 and the stage and type of pathology, which is model-dependent.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    TREM2 depletion dampens the effects of AD-tau injection, elevating the inflammatory response to near-control levels.

    “These data suggest that TREM2 depletion dampens the effects of AD-tau injection, elevating the inflammatory response to near-control levels (WT-PBS Figure 5B and Supplementary File S1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Gene expression changes measured in whole ipsilateral hemisphere by NanoString reflect microglial and astrocytic function.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The effect of TREM2 on tau propagation depends on the tau pathology stage or the tau seed's nature.

    “the effect of TREM2 on tau propagation depends on the tau pathology stage or the tau seed’s nature.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    TREM2 deficiency could influence astrocyte responses to tau propagation.

    “Our data also suggest that TREM2 deficiency could influence astrocyte responses to tau propagation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Reduced TREM2 signaling could render microglia vulnerable to pathological tau aggregates, enhancing their dysfunction, reducing the inflammatory response, and possibly inducing cell death, ultimately decreasing the ability of microglia to contribute to tau propagation.

    “reduced TREM2 signaling could render microglia vulnerable to pathological tau aggregates, enhancing their dysfunction, reducing the inflammatory response, and possibly inducing cell death, ultimately decreasing the ability of microglia to contribute to tau propagation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    TREM2 deficiency could solely affect one subset of astrocytes.

    “it is also reasonable to suggest that TREM2 deficiency could solely affect one subset of astrocytes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TREM2 is required for microglia to limit astrocyte synaptic engulfment during development.

    “a recent study demonstrated that TREM2 is required for microglia to limit astrocyte synaptic engulfment during development [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Jay, 2019, TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment, Glia source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The effect of TREM2 on tau propagation in an amyloid-dependent manner could depend on the disease stage.

    “the effect of TREM2 on tau propagation in an amyloid-dependent manner could depend on the disease stage.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In the APP/PS1 model, a decrease in GFAP-positive astrocytes but not S100β-positive astrocytes was observed.

    “a decrease in GFAP-positive astrocytes but not S100β-positive astrocytes was observed”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Jay, 2017, Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer’s Disease, J. Neurosci. source
52 of 52

  • The paper relies on this without support.

    AT8-positive tau pathology in brain regions not directly adjacent to the injection site reflects tau propagation rather than direct diffusion of injected AD-tau.

    “where the accumulation of pathological tau may be attributed to tau propagation”
    “areas not directly adjacent to the injection site where the accumulation of pathological tau may be attributed to tau propagation”

  • The paper relies on this without support.

    Gene expression changes measured in whole ipsilateral hemisphere by NanoString reflect microglial and astrocytic function.

    “we characterized the neuroinflammatory response to tau propagation in Trem2−/− mice using RNA extracted from whole-brain homogenates prepared from the ipsilateral hemisphere.”
2 of 2

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting results for the microglial function score

    Major

    The Figure 5B discussion says Trem2−/− AD-tau mice had decreased microglial function compared with WT AD-tau mice. The subsequent discussion of the microglial function score says there were no differences in any comparison involving Trem2−/− mice.

1 of 1

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Authors
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.
Affiliations
  • Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
  • Indiana University Indianapolis (US)
  • Purdue University West Lafayette (US)
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2023-06-10
Volume
12
Issue
12
Pages
1597
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells12121597
PMC
PMC10296847
OpenAlex
W4380373854
Semantic Scholar
5fee589c34b98e554447e5bf40bdc0691fd7e186
Cited by
19
References
50
Citations by year
2026: 6 · 2025: 5 · 2024: 6 · 2023: 2
FWCI
2.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Precision Health Initiative in Alzheimer’s Disease at Indiana University School of Medicine (1R01AG059639, 1R01AG080917, 1R01NS119280, AZ180006, 1937986)
  • NIH/NIA (1R01AG059639, 1R01AG080917, 1R01NS119280, AZ180006, 1937986)
  • NIH/NINDS (1R01AG059639, 1R01AG080917, 1R01NS119280, AZ180006, 1937986)
  • Department of Defense award (1R01AG059639, 1R01AG080917, 1R01NS119280, AZ180006, 1937986)
  • NSF CBET (1R01AG059639, 1R01AG080917, 1R01NS119280, AZ180006, 1937986)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
TREM2, microglia, tau propagation, Alzheimer's disease, tauopathy, TREM2 deficiency, neuroinflammation, microglial activation, tau aggregation, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Membrane Glycoproteins, Receptors, Immunologic, Signal Transduction, tau Proteins, Microglia, 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.

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Statistics and arithmetic are recomputed, not judged.

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