CoChat
Sign Up
Cited by 392Multiple Sclerosis Research StudiesNeuroinflammation and Neurodegeneration MechanismsPhagocytosis and Immune Regulation

TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis

Open access
Cignarella, Francesca, Filipello, Fabia, Bollman, Bryan, Cantoni, Claudia, Locca, Alberto, Mikesell, Robert, Manis, Melissa, Ibrahim, Adiljan +12 more·2020·Acta Neuropathologica
DOI 10.1007/s00401-020-02193-zPMC PMC7498497
Open this paper in CoChat — free accountOpen PDF

Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are critical for the clearance of myelin debris in areas of demyelination, a key step to allow remyelination. TREM2 is expressed by microglia and promotes microglial survival, proliferation, and phagocytic activity. Herein we demonstrate that TREM2 was highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of subjects with MS. In gene expression studies, macrophages from subjects with TREM2 genetic deficiency displayed a defect in phagocytic pathways. Treatment with a new TREM2 agonistic antibody promoted the clearance of myelin debris in the cuprizone model of CNS demyelination. Effects included enhancement of myelin uptake and degradation, resulting in accelerated myelin debris removal by microglia. Most importantly, antibody-dependent TREM2 activation on microglia increased density of oligodendrocyte precursors in areas of demyelination, as well as the formation of mature oligodendrocytes thus enhancing remyelination and axonal integrity. These results are relevant as they propose TREM2 on microglia as a potential new target to promote remyelination.

AI snapshot

Written from the paper’s full text.

TL;DR

In the cuprizone demyelination model, the TREM2 agonist antibody AL002a enhanced microglial myelin debris uptake and degradation, increased oligodendrocyte precursor density and maturation, and accelerated remyelination in Trem2+/− mice. TREM2 was highly expressed in active MS lesions, and macrophages from TREM2-deficient Nasu–Hakola patients showed downregulated phagocytic pathways.

Key findings

  • TREM2 was highly expressed by Iba1+ myelin-laden phagocytes in active MS lesions; TREM2 mRNA was significantly higher in active MS lesions than in MS NAWM or control white matter (7 active lesion samples from 5 MS patients vs 6 NAWM samples from 3 MS patients vs 7 control samples from 4 controls; P < 0.01).
  • AL002a acted as a TREM2 agonist: it induced DAP12 phosphorylation in Trem2+/+ but not Trem2−/− BMDM, activated TREM2 signaling in a reporter assay, and potentiated myelin-induced signaling at myelin concentrations >100 µg/ml.
  • In Trem2+/− mice after cuprizone, AL002a reduced dMBP at WK 4 + 3D, increased dMBP inside CD68+ phagolysosomes at WK 4, increased myelin uptake by BMDM at 1 h, and increased degradation at 24 and 48 h.
  • AL002a increased PDGFRα+ OPC density at WK 4 + 3D and WK 4 + 7D, increased OLIG2+ and CNPase+ cells, increased Mbp/Mag/Plp1 mRNA, and increased myelinated axons by TEM: 32% ± 0.0192 vs 23% ± 0.0122 at WK 4 + 3D and 53% ± 0.0124 vs 42% ± 0.0179 at WK 4 + 7D. Plasma Nf-L was lower with AL002a at WK 4 + 3D, and SMI-31 was higher at WK 4 + 7D.

Methods

  • Human CNS autopsy tissue from 8 MS patients and 4 non-neurological controls was analyzed by histology, confocal microscopy, and RT-qPCR; PBMC-derived macrophages from 3 Nasu–Hakola patients and 3 controls were analyzed by microarray.
  • Trem2+/+, Trem2+/−, and Trem2−/− C57BL/6 mice were fed 0.2% cuprizone for 4 weeks, then recovered for 3, 7, or 14 days; mice received AL002a or control antibody intraperitoneally at 80 mg/kg weekly, starting 4 days before cuprizone.
  • Analyses included BMDM phagocytosis/degradation assays, NFAT-luciferase TREM2 reporter assays, flow cytometry, immunohistochemistry, confocal 3D reconstruction, TEM/g-ratio, and Simoa Nf-L; statistics used ANOVA with post hoc tests, t tests, or Mann–Whitney tests, with P < 0.05 considered significant.

Limitations

  • The paper states that TREM2 function in human microglia remains elusive because of experimental difficulties and limitations of human studies.
  • The paper states that it is not fully clear whether enhanced remyelination after AL002a is due to accelerated myelin debris removal or an additional TREM2-mediated microglial signal recruiting OPCs; future studies are needed.
  • The paper notes that AL002a was tested in Trem2+/− mice because no effect was detected in Trem2+/+ mice, and that future studies are needed to clarify whether TREM2 activation directly enhances microglia proliferation in vivo; the cuprizone model is toxin-induced demyelination rather than autoimmune MS, and the human NHD gene-expression analysis used only 3 patients and 3 controls.

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

Integrity signals

Registry

Crossref · 10.1007/s00401-020-02193-z

Cites

54 of 54 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 48 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    TREM2 is expressed by microglia in the CNS, especially after activation.

    “The general consensus is that TREM2 is expressed by microglia in the CNS, especially after activation [6, 21, 47].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [6] Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G et al (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–143. https://doi.org/10.1038/nn.3599 source

      The Results sections on microglial gene signatures and surface molecules discuss other markers, including P2ry12, but do not address TREM2. Searches for TREM2 expression and activation found no passage in our copy establishing that TREM2 is expressed by CNS microglia, especially after activation. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [21] Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK et al (2017) A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169(1276–1290):e1217. https://doi.org/10.1016/j.cell.2017.05.018 source
    • cites [47] Ulland TK, Colonna M (2018) TREM2—a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 14:667–675. https://doi.org/10.1038/s41582-018-0072-1 source
  • Premisecitation

    Efficient myelin debris removal and clearance by phagocytic cells are critical to eliminate inhibitory signals interfering with OPC activation, recruitment to the site of demyelination and/or differentiation into myelinating mature oligodendrocytes.

    “Efficient myelin debris removal and clearance by phagocytic cells are critical to eliminate inhibitory signals interfering with OPC activation, recruitment to the site of demyelination and/or differentiation into myelinating mature OLs [14, 26, 27].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [14] Franklin RJM, Ffrench-Constant C (2017) Regenerating CNS myelin—from mechanisms to experimental medicines. Nat Rev Neurosci 18:753–769. https://doi.org/10.1038/nrn.2017.136 source

      In “Systemic factors and remyelination” (page not available), the review says phagocytic macrophages clear myelin debris containing inhibitors of OPC differentiation, and that clearance prevents interference with the final stage of remyelination. It does not say that those debris-borne inhibitors interfere with OPC activation or recruitment; its discussion of macrophages during recruitment concerns a different role. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [26] Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci Off J Soc Neurosci 26:328–332. https://doi.org/10.1523/JNEUROSCI.2615-05.2006 source
    • cites [27] Lampron A, Larochelle A, Laflamme N, Prefontaine P, Plante MM, Sanchez MG et al (2015) Inefficient clearance of myelin debris by microglia impairs remyelinating processes. J Exp Med 212:481–495. https://doi.org/10.1084/jem.20141656 source
  • Premisecitation

    Efficient clearance of myelin debris after demyelination can favorably impact OPC recruitment and differentiation into remyelinating oligodendrocytes.

    “Efficient clearance of myelin debris after demyelination can favorably impact OPC recruitment and differentiation into remyelinating oligodendrocytes [29].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [29] Lloyd AF, Miron VE (2019) The pro-remyelination properties of microglia in the central nervous system. Nat Rev Neurol 15:447–458. https://doi.org/10.1038/s41582-019-0184-2 source

      The available passages contain bibliographic details and the review’s title, but no discussion of myelin-debris clearance or its effects on OPC recruitment and differentiation. Searches for those terms and for phagocytosis found no passage addressing the claim, so our copy cannot verify it. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Premisecitation

    Trem2−/− mice present a significant defect in clearance of myelin debris in the CPZ-induced model of demyelination compared to Trem2+/+ mice.

    “We and others have previously shown that Trem2−/− mice present a significant defect in clearance of myelin debris in the CPZ-induced model of demyelination compared to Trem2+/+ mice [8, 42].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [8] Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R et al (2015) TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129:429–447. https://doi.org/10.1007/s00401-015-1388-1 source
    • cites [42] Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y, Gilfillan S et al (2015) TREM2 sustains microglial expansion during aging and response to demyelination. J Clin Investig 125:2161–2170. https://doi.org/10.1172/JCI77983 source
  • Findingcitation

    Only 11 genes, including TREM2, remained significant after adjustment of the absolute fold change cutoff to a FDR < 0.05.

    “Only 11 genes, including TREM2, remained significant after adjustment of the absolute fold change cutoff to a FDR < 0.05 [40] (Supplementary Table 1).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [40] Pawitan Y, Michiels S, Koscielny S, Gusnanto A, Ploner A (2005) False discovery rate, sensitivity and sample size for microarray studies. Bioinformatics 21:3017–3024. https://doi.org/10.1093/bioinformatics/bti448 source

      Section 2.1 describes using a fold-change statistic to set a cutoff for declaring genes differentially expressed, and Section 3.3 discusses extending FDR analysis to fold-change statistics. The paper does not report that 11 genes, including TREM2, remained significant, or document the claimed FDR < 0.05 result. Page numbers were not available in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 13
  • May combine two claims. 41

  • Classified as probably not a substantial claim.

    Premisecitation

    TREM2 is a phospholipid sensing receptor known to sustain microglial cell activation and expansion in response to demyelination or amyloid plaques in Alzheimer's disease.

    “TREM2 is a phospholipid sensing receptor known to sustain microglial cell activation and expansion in response to demyelination or amyloid plaques in Alzheimer’s disease (AD) [8, 42, 50].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [8] Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R et al (2015) TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129:429–447. https://doi.org/10.1007/s00401-015-1388-1 source

      The Abstract and the Results section on microglial proliferation report that TREM2 supports microglial activation and proliferation during cuprizone-induced demyelination. The Discussion also reports fewer plaque-associated microglia in an AD mouse model with one copy of TREM2, but does not establish that TREM2 sustains both activation and expansion at amyloid plaques. The Introduction says TREM2 ligands are poorly characterized; it does not identify TREM2 as a phospholipid-sensing receptor. Page numbers were not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [42] Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y, Gilfillan S et al (2015) TREM2 sustains microglial expansion during aging and response to demyelination. J Clin Investig 125:2161–2170. https://doi.org/10.1172/JCI77983 source

      The Introduction and Results report that TREM2 detects phospholipids and supports microglial activation in response to demyelination; the Abstract reports microglial expansion during aging. The Discussion only proposes that TREM2 may support a microglial response to β-amyloid plaques in Alzheimer’s disease, rather than establishing activation or expansion in response to those plaques. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [50] Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML et al (2015) TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160:1061–1071. https://doi.org/10.1016/j.cell.2015.01.049 source

      The Discussion states that TREM2 supports microglial expansion and activation around Aβ plaques in the 5XFAD Alzheimer’s disease model, and the Results identify it as a sensor for several lipids. The Discussion only suggests that TREM2 may trigger a microglial response to damaged myelin; it does not establish that TREM2 sustains microglial activation and expansion during demyelination. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Current MS immunomodulatory treatments target CNS inflammation, while therapies capable of regenerating myelin and halting disease progression are lacking.

    “Current MS immunomodulatory treatments target CNS inflammation, while therapies capable of regenerating myelin and halting disease progression are lacking [28].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [28] Lassmann H, Bruck W, Lucchinetti CF (2007) The immunopathology of multiple sclerosis: an overview. Brain Pathol 17:210–218. https://doi.org/10.1111/j.1750-3639.2007.00064.x source

      The Introduction says current anti-inflammatory and immunomodulatory treatments are partly effective early in MS but offer limited benefit in the progressive phase. Its remyelination discussion calls therapies that promote myelin repair an attractive option, but does not explicitly establish that such therapies are lacking; nor does it say that no therapy can halt disease progression. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    The cuprizone model is a well-established toxin-induced model of demyelination in the CNS.

    “Here, we explored the effect of antibody-mediated TREM2 activation on microglia in a well-established toxin-induced model of demyelination in the CNS resulting from exposure to the copper chelator cuprizone (CPZ) in the diet [31].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11:107–116 source

  • May combine two claims.

    Premisecitation

    In the cuprizone model, these events lead to OPC recruitment, differentiation into mature oligodendrocytes, and then remyelination which is almost complete within a few weeks from toxin withdrawal.

    “These events lead to OPC recruitment, differentiation into mature OLs, and then remyelination which is almost complete within few weeks from toxin withdrawal [31].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11:107–116 source

  • May combine two claims.

    Premisecitation

    Microglia activation and myelin debris clearance are critical steps for successful remyelination.

    “Microglia activation and myelin debris clearance are critical steps for successful remyelination [29].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [29] Lloyd AF, Miron VE (2019) The pro-remyelination properties of microglia in the central nervous system. Nat Rev Neurol 15:447–458. https://doi.org/10.1038/s41582-019-0184-2 source

      The available copy identifies the review as concerning the pro-remyelination properties of microglia, but the retrieved passages are bibliographic information rather than discussion of the proposed steps. Searches for microglial activation and myelin debris clearance found no passage establishing that either is critical for successful remyelination. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

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

    Premisecitation

    TREM2 clustering promotes calcium flux stimulating NFAT-activity that induces luciferase expression.

    “TREM2 clustering promotes calcium flux stimulating NFAT-activity that induces luciferase expression [50].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [50] Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML et al (2015) TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160:1061–1071. https://doi.org/10.1016/j.cell.2015.01.049 source

      The Results section (‘TREM2 is a sensor for anionic and zwitterionic lipids’) says that TREM2 engagement leads to calcium mobilization and NFAT-controlled reporter expression. But it identifies the reporter as GFP, not luciferase, and describes lipid engagement rather than TREM2 clustering. The Experimental Procedures (‘Reporter assay’) also measure GFP-positive cells. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Trem2−/− mice have a striking defect in microglia activation and myelin debris clearance in the CPZ model.

    “We previously showed that Trem2−/− mice have a striking defect in microglia activation and myelin debris clearance in the CPZ model [8].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R et al (2015) TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129:429–447. https://doi.org/10.1007/s00401-015-1388-1 source

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

    Premisecitation

    A role of TREM2 in phagocytic pathways in the human brain was previously suggested.

    “A role of TREM2 in phagocytic pathways in the human brain was previously suggested [13].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Forabosco P, Ramasamy A, Trabzuni D, Walker R, Smith C, Bras J et al (2013) Insights into TREM2 biology by network analysis of human brain gene expression data. Neurobiol Aging 34:2699–2714. https://doi.org/10.1016/j.neurobiolaging.2013.05.001 source

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

    Premisecitation

    TREM2 is involved in microglia phagocytosis of apoptotic neurons, myelin, and β-amyloid.

    “TREM2 has often been referred to as a phagocytic receptor as it was demonstrated to be involved in microglia phagocytosis of apoptotic neurons [46], myelin [8] and β-amyloid [24].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [46] Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201:647–657 source
    • cites [8] Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R et al (2015) TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129:429–447. https://doi.org/10.1007/s00401-015-1388-1 source
    • cites [24] Kleinberger G, Yamanishi Y, Suarez-Calvet M, Czirr E, Lohmann E, Cuyvers E et al (2014) TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med 6:243ra286. https://doi.org/10.1126/scitranslmed.3009093 source

  • May combine two claims.

    Interpretationcitation

    TREM2 has a more complex function not only in myelin uptake, but also in promoting myelin debris degradation through the phagolysosomal pathway.

    “However, our current and previous findings indicate a more complex TREM2 function not only in myelin uptake, but also in promoting myelin debris degradation through the phagolysosomal pathway [8].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R et al (2015) TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129:429–447. https://doi.org/10.1007/s00401-015-1388-1 source

      The Results section ('Defective myelin degradation by microglia in TREM2−/− mice'; page unavailable) finds impaired myelin breakdown and persistent myelin-filled phagosomes in TREM2-deficient mice, supporting a role for TREM2 in degradation. But it reports no difference in myelin uptake and says the findings do not support an uptake defect. It implicates phagosome processing without establishing the specific phagolysosomal pathway claimed. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    TREM2 is highly expressed within active MS lesions by lipid-laden microglia/macrophages known to display an alternatively activated M2 profile and to promote the resolution of inflammation and clearance of myelin debris.

    “Here we show that TREM2 was highly expressed within active MS lesions by lipid-laden microglia/macrophages known to display an alternatively activated M2 profile and to promote the resolution of inflammation and clearance of myelin debris [5].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [5] Boven LA, Van Meurs M, Van Zwam M, Wierenga-Wolf A, Hintzen RQ, Boot RG et al (2006) Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis. Brain 129:517–526 source

      The Introduction describes foamy macrophages in MS lesions as myelin-scavenging cells derived from microglia or monocytes, and the results say they resemble anti-inflammatory M2 macrophages. The Discussion says they are *likely* to contribute to resolution of inflammation; it does not establish that they promote resolution as a demonstrated function. The TREM2-expression finding is introduced as the citing authors’ own result, not one attributed to this source. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    TREM2 is not a limiting factor in myelin engulfment, but is essential for microglia capacity to degrade myelin during chronic demyelination.

    “In our previous work, we provided initial evidence to support this hypothesis by showing that TREM2 is not a limiting factor in myelin engulfment, but it was clearly essential for microglia capacity to degrade myelin during chronic demyelination [8].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R et al (2015) TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129:429–447. https://doi.org/10.1007/s00401-015-1388-1 source

  • May combine two claims.

    Findingown data

    AL002a binds wild-type Trem2+/+ but not Trem2−/− thioglycollate-induced macrophages.

    “The antibody’s specificity was verified by binding to wild-type (Trem2+/+), but not Trem2−/− thioglycollate-induced macrophages (THG-Mac) (Supplementary Fig. 1a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TREM2 is specifically expressed in Iba1+ cells in active MS lesions, which were identified as oil-red O+ lipid-laden macrophages-microglia by histology.

    “By confocal analysis we showed TREM2 specific expression in ionized calcium-binding adapter molecule 1(Iba1)+ cells in active MS lesion, which were identified as oil-red O+ lipid laden macrophages-microglia by histology (Fig. 1a, b).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Principal component analysis showed the ability of gene expression data to discriminate NHD from control subjects.

    “Principal component analysis showed the ability of gene expression data to discriminate NHD from control subjects (Supplementary Fig. 4e).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Significantly more myelinated axons were counted in the corpus callosum after AL002a treatment compared to control at WK 4 + 3D (32% vs 23%) and at WK 4 + 7D (53% vs 42%).

    “Significantly more MA were counted in the CC after AL002a treatment compared to control at WK 4 + 3D (MA: 32% ± 0.0192 in AL002a-treated group vs. MA: 23% ± 0.0122 in control group) and this was even more pronounced at WK 4 + 7D (MA: 53% ± 0.0124 in AL002a-treated group vs. MA:42% ± 0.0179 in control group) (Fig. 7j).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Genes from the phagocytic pathway are both significantly co-expressed with TREM2 and altered in NHD patients.

    “A GO cellular component analysis confirmed that genes from the phagocytic pathway are both significantly co-expressed with TREM2 and altered in NHD patients (Supplementary Table 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AL002a treatment was accompanied by increased microglia activation and higher expression of proteins involved in phagocytic and degradative pathways.

    “This was accompanied by increased microglia activation and by a higher expression of proteins involved in phagocytic and degradative pathways.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AL002a treatment in Trem2+/− mice with CPZ-induced CNS demyelination resulted in significantly lower plasma Nf-L levels at WK 4 + 3D compared to control antibody, with a trend of reduced levels at WK 4 + 7D.

    “Mice treated with AL002a showed significantly lower Nf-L levels in the plasma at WK 4 + 3D compared to the control, with a trend of reduced levels also observed at WK 4 + 7D (Fig. 8a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In vitro, MBP internalization by Trem2+/− BMDM was significantly increased with AL002a after 1 h, while no differences were detected at 30 min and 3 h.

    “Analysis of MBP internalization by immunofluorescence revealed a significant increase in MBP amount detected inside Iba1+ cells treated with AL002a after 1 h (Fig. 5d, e), while no differences between the two groups were detected at 30’ and 3 h.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment with AL002a in vivo promotes efficient clearance of myelin debris, with increased myelin phagocytosis and intracellular degradation after CPZ-induced demyelination.

    “We then demonstrated that treatment with AL002a in vivo promotes efficient clearance of myelin debris, with increased myelin phagocytosis and intracellular degradation after CPZ-induce demyelination.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AL002a treatment increased OPC density and differentiation into mature OL.

    “AL002a treatment increased OPC density and differentiation into mature OL”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AL002a was able to reach the brain and was detected in the corpus callosum and cortex.

    “AL002a was able to reach the brain and it was detected in the CC and in the cortex (Ctx) (Supplementary Fig. 1d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Gene ontology analysis revealed that genes involved in the phagosome pathway are among the top pathways significantly altered in NHD subjects compared to controls, along with changes in immune response pathways.

    “Gene ontology (GO) analysis revealed that genes involved in the phagosome pathway are among the top-pathways significantly altered in NHD subjects compared to controls along with changes in immune response pathways (Fig. 9b, and Supplementary Table 2 and 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AL002a is a potent TREM2 agonist antibody capable of activating TREM2 in vitro and in vivo and potentiating myelin-induced activation of TREM2 signaling.

    “Our data demonstrate that AL002a is a potent TREM2 agonist antibody capable of activating TREM2 in vitro and in vivo and to potentiate myelin-induced activation of TREM2 signaling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AL002a treatment was accompanied by increased microglia expression of markers of activation (Iba1 and CD80) and phagolysosomal activity (CD68 and LAMP1).

    “This was accompanied by increased microglia expression of markers of activation (Iba1 and CD80) and phagolysosomal activity (CD68 and LAMP1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the current study, no differences in the number of microglia were detected between Trem2+/− and Trem2+/+ mice at 4 weeks on CPZ, despite more myelin debris accumulating in the CC of Trem2+/−.

    “Interestingly, in the current study at this time point no differences in the number of microglia were detected between Trem2+/− and Trem2+/+ mice, despite more myelin debris were accumulating in the CC of Trem2+/−.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In Trem2+/+ mice treated with AL002a, no difference was detected in damaged myelin accumulation, number of microglia or OPC in the CC compared to control at 4 weeks on CPZ.

    “First, we tested AL002a in Trem2+/+ mice, without detecting any difference in damaged myelin accumulation, number of microglia or OPC in the CC compared to the control group at 4 weeks on CPZ (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TREM2 engagement leads to DAP12 phosphorylation, followed by recruitment and activation of SYK, resulting in downstream signaling events leading to proliferation, survival, phagocytosis, and secretion of cytokines and chemokines.

    “TREM2 engagement leads to DAP12 phosphorylation, followed by recruitment and activation of the spleen-associated tyrosine kinase (SYK), resulting in downstream signaling events leading to proliferation, survival, phagocytosis, and secretion of cytokines and chemokines [47].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Ulland TK, Colonna M (2018) TREM2—a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 14:667–675. https://doi.org/10.1038/s41582-018-0072-1 source

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

    Premisecitation

    Microglial cells and infiltrating monocytes/macrophages can have a dual role in MS lesions: they may contribute to myelin damage and lesion expansion, or they may have a protective role by clearing myelin debris, reducing inflammation and secreting regenerative factors promoting remyelination.

    “Microglial cells and infiltrating monocytes/macrophages can have a dual role in MS lesions. They could contribute to myelin damage and lesion expansion, or they may have a protective role by clearing myelin debris, reducing inflammation and secreting regenerative factors promoting remyelination [48].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Voet S, Prinz M, van Loo G (2019) Microglia in central nervous system inflammation and multiple sclerosis pathology. Trends Mol Med 25:112–123. https://doi.org/10.1016/j.molmed.2018.11.005 source

  • May combine two claims.

    Interpretationown data

    TREM2 on microglia is a potential new target to promote remyelination and a potential novel therapeutic avenue in MS and other demyelinating disorders.

    “These results are relevant as they propose TREM2 on microglia as a potential new target to promote remyelination.”
    • Also stated in: § Introduction · hedged
      “This provides the proof of concept that antibody-mediated TREM2 activation could promote remyelination, suggesting this as a potential novel therapeutic avenue in MS and other demyelinating disorders.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The cuprizone-induced demyelination model is a valid model of multiple sclerosis for evaluating remyelination-promoting therapies.
    • Rests on an assumption: Antibody-mediated TREM2 activation in the cuprizone model is predictive of therapeutic benefit in MS.

  • May combine two claims.

    Premisecitation

    In MS, impaired generation of oligodendrocytes from OPCs leads to persistent demyelination, myelin debris accumulation, and axonal damage, which clinically manifests as neurological disability.

    “In MS, impaired generation of OLs from OPCs leads to persistent demyelination, myelin debris accumulation, and axonal damage which clinically manifests as neurological disability [11].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Dulamea AO (2017) Role of oligodendrocyte dysfunction in demyelination, remyelination and neurodegeneration in multiple sclerosis. Adv Exp Med Biol 958:91–127. https://doi.org/10.1007/978-3-319-47861-6_7 source

  • Classified as probably not a substantial claim.

    Premisecitation

    TREM2 is an innate immune receptor expressed by several myeloid cells including brain microglia.

    “A critical modulator of microglia functions is the triggering receptor expressed on myeloid cells-2 (TREM2), an innate immune receptor expressed by several myeloid cells including brain microglia [23, 45].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Kiialainen A, Hovanes K, Paloneva J, Kopra O, Peltonen L (2005) Dap12 and Trem2, molecules involved in innate immunity and neurodegeneration, are co-expressed in the CNS. Neurobiol Dis 18:314–322 source
    • cites [45] Schmid CD, Sautkulis LN, Danielson PE, Cooper J, Hasel KW, Hilbush BS et al (2002) Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J Neurochem 83:1309–1320 source

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

    Premisecitation

    Homozygous loss-of-function mutations in TREM2 or DAP12 genes cause Nasu-Hakola disease, a rare genetic disorder characterized by fatal presenile dementia and bone cysts.

    “Homozygous loss-of-function mutations in TREM2 or DAP12 genes cause Nasu–Hakola disease (NHD), a rare genetic disorder characterized by fatal presenile dementia and bone cysts [38, 39].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] Paloneva J, Kestila M, Wu J, Salminen A, Bohling T, Ruotsalainen V et al (2000) Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet 25:357–361. https://doi.org/10.1038/77153 source
    • cites [39] Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R et al (2002) Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet 71:656–662 source

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

    Premisecitation

    TREM2 binds on the membrane to DAP12, an adaptor protein required for TREM2 surface expression and intracellular signaling.

    “TREM2 binds on the membrane to the DNAX-activation protein 12 (DAP12) which is an adaptor protein required for TREM2 surface expression and intracellular signaling [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Ulland TK, Colonna M (2018) TREM2—a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 14:667–675. https://doi.org/10.1038/s41582-018-0072-1 source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    AL002a was screened for TREM2 specificity by selecting for binding to wild-type but not Trem2−/− BMDM.

    “AL002a was screened for TREM2 specificity by selecting for binding to wild-type (Trem2+/+), but not Trem2−/− BMDM.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Neuropathological findings in Nasu-Hakola disease include loss of myelin and axons in the brain, with reactive astrocytosis and microglial activation.

    “Neuropathological findings in NHD include loss of myelin and axons in the brain, with reactive astrocytosis and microglial activation [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Klunemann HH, Ridha BH, Magy L, Wherrett JR, Hemelsoet DM, Keen RW et al (2005) The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 64:1502–1507 source

  • May combine two claims.

    Interpretationown data

    AL002a treatment preserved axonal health during CPZ treatment, preventing neurodegeneration.

    “In conclusion, AL002a treatment preserved axonal health during CPZ treatment, thus preventing neurodegeneration.”
    • Also stated in: § Discussion · hedged
      “Importantly, our study has also shown that AL002a treatment after CPZ is associated with reduced Nf-L plasma levels (a markers of axonal/neuronal damage), suggesting that increased remyelination also results in preserved axonal integrity, further proven by increased SMI31 staining in the CC of AL002a-treated mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    AL002a is a potent inducer of TREM2 intracellular signaling in vitro by both cross-linking and soluble stimulation and in vivo by soluble stimulation.

    “These results demonstrate that AL002a is a potent inducer of TREM2 intracellular signaling in vitro (by both cross-linking and soluble stimulation) and in vivo (by soluble stimulation).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These data from NHD individuals confirmed that TREM2 receptor plays a critical role in phagocytic pathways in human myeloid cells and that during NHD pathology genes involved in phagocytosis are specifically dysregulated.

    “Overall, these data from NHD individuals, confirmed that TREM2 receptor plays a critical role in phagocytic pathways in human myeloid cells and that during NHD pathology genes involved in phagocytosis are specifically dysregulated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Trem2 haploinsufficiency leads to inefficient myelin debris clearance and reduced OPC recruitment, even if it does not impact the number of microglia accumulating in the corpus callosum.

    “Trem2 haploinsufficiency leads to inefficient myelin debris clearance, reduced OPC recruitment, even if it does not impact on the number of microglia accumulating in the CC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    AL002a leads to a significant increase in myelin phagocytosis by Trem2+/− BMDM after 1 h and accelerates their degradative capacity at later time points.

    “Therefore, AL002a leads to a significant increase in myelin phagocytosis by Trem2+/− BMDM after 1 h, and also it accelerates their degradative capacity at later time points.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    AL002a acts as a potent TREM2 agonist both in vitro and in vivo, and its agonistic activity is boosted by the presence of myelin.

    “In conclusion, our data demonstrate that AL002a acts as a potent TREM2 agonist both in vitro and in vivo, and its agonistic activity is boosted by the presence of myelin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    AL002a antibody treatment enhanced myelin debris internalization by microglia at WK 4, as demonstrated by higher dMBP amount inside CD68+ structures in microglia, accompanied by decreased dMBP total volume per field at WK 4 + 3D.

    “These findings suggest that AL002a antibody treatment enhanced myelin debris internalization by microglia at WK 4, as demonstrated by a higher dMBP amount detected inside CD68+ structures in microglia (Fig. 5a, c), accompanied by decreased dMBP total volume per field (Fig. 4b, c) at WK 4 + 3D.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    AL002a is a strong inducer of DAP12 phosphorylation after cross-linking and as soluble, and acts as an agonist of TREM2 signaling.

    “These results demonstrate that AL002a is a strong inducer of DAP12 phosphorylation (after cross-linking and as soluble), and it acts as an agonist of TREM2 signaling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The presence of a fully functional TREM2 receptor on microglia is critical for efficient myelin debris removal and quick OPC recruitment observed in Trem2+/+ mice.

    “These results suggest that the presence of a fully functional TREM2 receptor on microglia is critical for efficient myelin debris removal and quick OPC recruitment observed in Trem2+/+ mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Strategies aimed at targeting TREM2 on microglia in the CNS are feasible and might be a promising intervention in MS to promote microglia functions in clearing myelin debris, favoring the recruitment of OPCs, and their subsequent differentiation into mature myelin-generating oligodendrocytes, eventually leading to remyelination and axonal protection.

    “Altogether our study indicates that strategies aimed at targeting TREM2 on microglia in the CNS are feasible and might be a promising intervention in MS to promote microglia functions in clearing myelin debris, favoring the recruitment of OPCs, and their subsequent differentiation into mature myelin-generating oligodendrocytes, eventually leading to remyelination and axonal protection.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Currently, no therapies are available to regenerate myelin and to halt MS disease progression.

  • May combine two claims.

    Premisecitation

    NHD is characterized by loss of myelin and microglia activation in the CNS.

    “NHD is characterized by loss of myelin and microglia activation in the CNS [25].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Klunemann HH, Ridha BH, Magy L, Wherrett JR, Hemelsoet DM, Keen RW et al (2005) The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 64:1502–1507 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Remyelination protects axons from ongoing degeneration.

    “Remyelination is known to protect axons from ongoing degeneration [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Irvine KA, Blakemore WF (2008) Remyelination protects axons from demyelination-associated axon degeneration. Brain 131:1464–1477. https://doi.org/10.1093/brain/awn080 source

  • May combine two claims.

    Interpretationown data

    One copy of TREM2 is sufficient to sustain microglia expansion after CPZ-induced damage, but cannot support a fully functional response by microglia to clear the conspicuous amount of myelin debris derived from massive oligodendrocyte death.

    “This could suggest that one copy of TREM2 is sufficient to sustain microglia expansion after CPZ-induced damage, but cannot support a fully functional response by microglia to clear the conspicuous amount of myelin debris derived from massive oligodendrocyte death.”
    Quote in the paperSubstantial claim
50 of 50

  • The paper relies on this without support.

    The cuprizone-induced demyelination model is a valid model of multiple sclerosis for evaluating remyelination-promoting therapies.

    “TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis”
    “Here, we explored the effect of antibody-mediated TREM2 activation on microglia in a well-established toxin-induced model of demyelination in the CNS resulting from exposure to the copper chelator cuprizone (CPZ) in the diet [31].”

  • The paper relies on this without support.

    Antibody-mediated TREM2 activation in the cuprizone model is predictive of therapeutic benefit in MS.

    “This provides the proof of concept that antibody-mediated TREM2 activation could promote remyelination, suggesting this as a potential novel therapeutic avenue in MS and other demyelinating disorders.”

  • The paper relies on this without support.

    A systematic characterization of TREM2 expression on microglia-macrophages in different types of MS lesions has not been done.

    “Yet, a systematic characterization of TREM2 expression on microglia-macrophages in different types of MS lesions has not been done.”

  • The paper relies on this without support.

    Whether heterozygous (Trem2+/−) mice would present the same or a milder phenotype than Trem2−/− mice has not been evaluated before in the CPZ model.

    “Whether heterozygous (Trem2+/−) mice would present the same or a milder phenotype than Trem2−/− mice has not been evaluated before in the CPZ model.”

  • The paper relies on this without support.

    Microglia internalize and phagocytose myelin, which is then degraded intracellularly by lysosomal structures.

    “Microglia internalize and phagocytose myelin which is then degraded intracellularly by lysosomal structures.”

  • The paper relies on this without support.

    Currently, no therapies are available to regenerate myelin and to halt MS disease progression.

    “Currently, no therapies are available to regenerate myelin and to halt MS disease progression.”

  • The paper relies on this without support.

    Trem2+/+ mouse microglia are very efficient in supporting complete remyelination in the acute CPZ model.

    “On the other end, it is well known that Trem2+/+ mouse microglia are very efficient in supporting complete remyelination in the acute CPZ model.”

  • The paper relies on this without support.

    In MS, a defect in TREM2 pathways has not been demonstrated, but remyelination fails in most cases.

    “This is different from what observed in MS, where a defect in TREM2 pathways has not been demonstrated, but still remyelination fails in most cases.”
8 of 8

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?

  • The clearance of myelin debris by microglia is believed to be critically required to limit neuronal damage in EAE.

    “In particular, the clearance of myelin debris by microglia is believed to be critically required to limit neuronal damage in EAE (Cignarella et al., 2020; Takahashi et al., 2007; Weinger et al., 2011).”

    From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Cignarella et al., 2020

    The Introduction and Discussion link microglial myelin-debris clearance to remyelination and axonal protection, and the Results report improved axonal health alongside enhanced clearance. However, the experiments used cuprizone-induced demyelination, not EAE, so the source does not establish that clearance is critically required to limit neuronal damage in EAE. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Feeding Sykcon mice a cuprizone diet leads to increased staining of phagocytic marker CD68 in Iba1+ cells.

    “Consistent with previous studies, we found that feeding Sykcon mice a cuprizone diet leads to increased staining of the phagocytic marker CD68 in Iba1+ cells (Figures S6G and S6H) (Cignarella et al., 2020).”

    From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Cignarella et al., 2020

    The Methods section (page unavailable) describes measuring CD68 staining colocalized with Iba1+ cells. The Results (Fig. 6, page unavailable) quantify that staining in cuprizone-fed Trem2+/− mice, comparing anti-TREM2 antibody treatment with a control. The paper does not study Sykcon mice or establish that the cuprizone diet itself increased CD68 staining relative to a non-cuprizone diet. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Mice lacking TREM2 also experience greater axonal damage after cuprizone treatment.

    “Mice lacking TREM2 also experience greater axonal damage after cuprizone treatment.”

    From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [202]

    The Results section, “AL002a treatment preserves axonal integrity” (page unavailable), reports markers of greater axonal damage in control-treated Trem2+/− mice than in those given a TREM2-activating antibody after cuprizone treatment. That supports an axonal-health effect of reduced TREM2 activity, but the axonal comparison is in heterozygous mice, not mice entirely lacking TREM2 (Trem2−/−). (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • In mice lacking TREM2, fewer microglia accumulate in the corpus callosum during demyelination due to reduced proliferation, which in turn reduces myelin debris clearance.

    “In mice lacking TREM2, fewer microglia accumulate in the corpus callosum during demyelination due to reduced proliferation which in turn reduces myelin debris clearance [200–202].”

    From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [202]

    The Results section reports fewer microglia and more myelin debris in the corpus callosum of Trem2−/− mice after four weeks of cuprizone-induced demyelination. The Discussion says the authors previously found reduced microglial proliferation, but says this *could contribute* to impaired debris clearance; it does not establish the causal chain stated in the claim. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • TREM2 agonists accelerate myelin clearance in the cuprizone model to facilitate remyelination.

    “Conversely, TREM2 agonists accelerate myelin clearance in the cuprizone model to facilitate remyelination [202] (Fig. 4J).”

    From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [202]

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.

  • Myelin-gene result names Mag, but Fig. 7 names Mog

    Minor

    The results identify the measured gene as Mag, whereas the Fig. 7 caption identifies the corresponding panel as Mog. The qPCR methods also list a Mog probe, not a Mag probe.

  • GFAP result is described as a cell count, but methods specify stained area

    Minor

    The results describe a comparison of the number of GFAP-positive cells. The methods instead state that GFAP was quantified as the area of positive staining, which is a different measurement.

2 of 2

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Cignarella, F., Filipello, F., Bollman, B., Cantoni, C., Locca, A., Mikesell, R., Manis, M., Ibrahim, A., Deng, L., Benitez, B. A., Cruchaga, C., Licastro, D., Mihindukulasuriya, K., Harari, O., Buckland, M., Holtzman, D. M., Rosenthal, A., Schwabe, T., Tassi, I., & Piccio, L.
Affiliations
  • Washington University in St. Louis (US)
  • Humanitas University (IT)
  • Alector (United States) (US)
  • AREA Science Park (IT)
  • The University of Sydney (AU)
Corresponding author
  • Tassi, Ilaria
  • Piccio, Laura
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2020-08-09
Volume
140
Issue
4
Pages
513-534
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-020-02193-z
PMC
PMC7498497
OpenAlex
W3048044439
Cited by
392
References
54
Citations by year
2026: 63 · 2025: 67 · 2024: 74 · 2023: 76 · 2022: 64 · 2021: 41 · 2020: 6 · 2012: 1
FWCI
26.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
Funders
  • NIA (RF1AG058501)
  • Alector
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
TREM2, microglia, multiple sclerosis, remyelination, myelin debris clearance, phagocytosis, cuprizone model, demyelination, oligodendrocyte precursor cells, oligodendrocyte differentiation, axonal integrity, macrophages
MeSH terms
Remyelination, Adult, Aged, Animals, Disease Models, Animal, Female, Humans, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Middle Aged, Multiple Sclerosis, Myelin Sheath, Phagocytosis, Receptors, Immunologic, Microglia, Mice, Knockout, 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 2026-10-13.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-13.

Cited sources are checked by gpt-6-sol.

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