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Cited by 519Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

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TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy

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Leyns, Cheryl E. G., Ulrich, Jason D., Finn, Mary B., Stewart, Floy R., Koscal, Lauren J., Remolina Serrano, Javier, Robinson, Grace O., Anderson, Elise, Colonna, Marco, Holtzman, David M.·2017·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1710311114PMC PMC5663386
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Abstract

Significance: Alzheimer’s disease (AD) is the most common cause of dementia and is a major public health problem for which there is currently no disease-modifying treatment. There is an urgent need for greater understanding of the molecular mechanisms underlying neurodegeneration in patients to create better therapeutic options. Recently, genetic studies uncovered novel AD risk variants in the microglial receptor, triggering receptor expressed on myeloid cells 2 (TREM2). Previous studies suggested that loss of TREM2 function worsens amyloid-β (Aβ) plaque-related toxicity. In contrast, we observe TREM2 deficiency mitigates neuroinflammation and protects against brain atrophy in the context of tau pathology. These findings indicate dual roles for TREM2 and microglia in the context of amyloid versus tau pathology, which are important to consider for potential treatments targeting TREM2.

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Figures

Fig. 1. TREM2 deficiency attenuates neurodegeneration in PS19 mice. (A) Representative images of Nissl staining from T2+/+PS and T2−/−PS mice. (Scale bars, 2.5 mm.) Quantification of the average volume of the (B) ventricles (P = 0.0034; T2+/+PS, n = 15; T2−/−PS, n = 19), (C) entorhinal and piriform cortex (P = 0.0232; T2+/+PS, n = 14; T2−/−PS, n = 17), and (D) hippocampus (P = 0.4589; T2+/+PS, n = 15; T2−/−PS, n = 20). (E) Immunoblot analysis from hippocampal RIPA lysates of PDS-95 in T2+/+PS and T2−/−PS mice. ERK served as a loading control. (F) Quantification of the relative protein levels for PSD-95 to the internal control, ERK1. Blots shown in E are cropped. Full-length blots are presented in Fig. S1. A Mann–Whitney test was used to determine statistical significance for ventricular volume due to the nonparametric data set. For all other graphs, significance was determined by an unpaired, two-tailed Student’s t test. Significance was defined as *P < 0.05 and **P < 0.01.
Fig. 1. TREM2 deficiency attenuates neurodegeneration in PS19 mice. (A) Representative images of Nissl staining from T2+/+PS and T2−/−PS mice. (Scale bars, 2.5 mm.) Quantification of the average volume of the (B) ventricles (P = 0.0034; T2+/+PS, n = 15; T2−/−PS, n = 19), (C) entorhinal and piriform cortex (P = 0.0232; T2+/+PS, n = 14; T2−/−PS, n = 17), and (D) hippocampus (P = 0.4589; T2+/+PS, n = 15; T2−/−PS, n = 20). (E) Immunoblot analysis from hippocampal RIPA lysates of PDS-95 in T2+/+PS and T2−/−PS mice. ERK served as a loading control. (F) Quantification of the relative protein levels for PSD-95 to the internal control, ERK1. Blots shown in E are cropped. Full-length blots are presented in Fig. S1. A Mann–Whitney test was used to determine statistical significance for ventricular volume due to the nonparametric data set. For all other graphs, significance was determined by an unpaired, two-tailed Student’s t test. Significance was defined as *P < 0.05 and **P < 0.01.CC BY-NC-ND · PubMed Central
Fig. S1. Full scans of immunoblot data. Unedited film from PSD-95 (∼83-kDa) and ERK1/2 (∼44- and 42-kDa) immunoblots.
Fig. S1. Full scans of immunoblot data. Unedited film from PSD-95 (∼83-kDa) and ERK1/2 (∼44- and 42-kDa) immunoblots.CC BY-NC-ND · PubMed Central
Fig. 2. No differences were observed in tau phosphorylation or solubility in 9-mo-old T2+/+PS and T2−/−PS mice. Quantification of the percent area covered by biotinylated AT8 staining in the (A) piriform cortex (P = 0.9499; T2+/+PS, n = 13; T2−/−PS, n = 21) and (B) hippocampus (P = 0.0652; T2+/+PS, n = 13; T2−/−PS, n = 20). Representative images of biotinylated AT8 p-tau staining in the (C) piriform cortex and (D) hippocampus from T2+/+PS and T2−/−PS mice. (Scale bars, 1 mm.) (E) Tau solubility in the hippocampus was quantified using a human-tau (htau) specific sandwich ELISA to measure (Left) RAB-soluble htau (P = 0.8562; T2+/+PS, n = 14; T2−/−PS, n = 17), (Center) RIPA-soluble htau (P = 0.1233; T2+/+PS, n = 14; T2−/−PS, n = 17), and (Right) FA-soluble htau levels (P = 0.9584; T2+/+PS, n = 14; T2−/−PS, n = 17). Data are presented as mean ± SEM. Significance was determined using an unpaired, two-tailed Student’s t test.
Fig. 2. No differences were observed in tau phosphorylation or solubility in 9-mo-old T2+/+PS and T2−/−PS mice. Quantification of the percent area covered by biotinylated AT8 staining in the (A) piriform cortex (P = 0.9499; T2+/+PS, n = 13; T2−/−PS, n = 21) and (B) hippocampus (P = 0.0652; T2+/+PS, n = 13; T2−/−PS, n = 20). Representative images of biotinylated AT8 p-tau staining in the (C) piriform cortex and (D) hippocampus from T2+/+PS and T2−/−PS mice. (Scale bars, 1 mm.) (E) Tau solubility in the hippocampus was quantified using a human-tau (htau) specific sandwich ELISA to measure (Left) RAB-soluble htau (P = 0.8562; T2+/+PS, n = 14; T2−/−PS, n = 17), (Center) RIPA-soluble htau (P = 0.1233; T2+/+PS, n = 14; T2−/−PS, n = 17), and (Right) FA-soluble htau levels (P = 0.9584; T2+/+PS, n = 14; T2−/−PS, n = 17). Data are presented as mean ± SEM. Significance was determined using an unpaired, two-tailed Student’s t test.CC BY-NC-ND · PubMed Central
Fig. 3. TREM2 deficiency reduces microgliosis in PS19 mice. Quantification of the percent area covered by Iba1 staining in the (A) piriform cortex (P = 0.0242; T2+/+PS, n = 14; T2−/−PS, n = 21) and (B) hippocampus (P = 0.0266; T2+/+PS, n = 14; T2−/−PS, n = 21). Representative images of Iba1 staining in the (C) piriform cortex and (D) hippocampus from T2+/+PS and T2−/−PS mice. (Scale bars, 1 mm.) (E) Quantification of immunofluorescence staining for Iba1-positive cell bodies in the piriform cortex (P = 0.0478; T2+/+PS, n = 12; T2−/−PS, n = 20). (F) Representative images of Iba1 immunofluorescence staining in the piriform cortex. Microglia in T2+/+PS mice display a more ramified phenotype as opposed to in T2−/−PS mice where microglia appear quiescent. Images represent maximum-intensity projections of z stacks. (Scale bars, 50 µm.) Data are mean ± SEM. Significance was determined using an unpaired, two-tailed Student’s t test with *P < 0.05.
Fig. 3. TREM2 deficiency reduces microgliosis in PS19 mice. Quantification of the percent area covered by Iba1 staining in the (A) piriform cortex (P = 0.0242; T2+/+PS, n = 14; T2−/−PS, n = 21) and (B) hippocampus (P = 0.0266; T2+/+PS, n = 14; T2−/−PS, n = 21). Representative images of Iba1 staining in the (C) piriform cortex and (D) hippocampus from T2+/+PS and T2−/−PS mice. (Scale bars, 1 mm.) (E) Quantification of immunofluorescence staining for Iba1-positive cell bodies in the piriform cortex (P = 0.0478; T2+/+PS, n = 12; T2−/−PS, n = 20). (F) Representative images of Iba1 immunofluorescence staining in the piriform cortex. Microglia in T2+/+PS mice display a more ramified phenotype as opposed to in T2−/−PS mice where microglia appear quiescent. Images represent maximum-intensity projections of z stacks. (Scale bars, 50 µm.) Data are mean ± SEM. Significance was determined using an unpaired, two-tailed Student’s t test with *P < 0.05.CC BY-NC-ND · PubMed Central
Fig. S2. No effect of TREM2 deficiency on KI-67–positive microglia in the piriform cortex. (A) Quantification of KI-67–positive microglia in the piriform cortex (P = 0.6844; T2+/+PS: 0.9725 ± 0.2171, n = 13; T2−/−PS: 0.8738 ± 0.2406, n = 22). (B) Representative image of KI-67–positive microglia. Images represent maximum-intensity projections of z stacks. (Scale bars: 50 µm.) Data are mean ± SEM. Significance was determined using an unpaired, two-tailed Student’s t test with *P < 0.05.
Fig. S2. No effect of TREM2 deficiency on KI-67–positive microglia in the piriform cortex. (A) Quantification of KI-67–positive microglia in the piriform cortex (P = 0.6844; T2+/+PS: 0.9725 ± 0.2171, n = 13; T2−/−PS: 0.8738 ± 0.2406, n = 22). (B) Representative image of KI-67–positive microglia. Images represent maximum-intensity projections of z stacks. (Scale bars: 50 µm.) Data are mean ± SEM. Significance was determined using an unpaired, two-tailed Student’s t test with *P < 0.05.CC BY-NC-ND · PubMed Central
Fig. S3. Correlations between tau pathology, microgliosis, and degeneration in the hippocampus of T2+/+PS and T2−/−PS mice. Significant correlations were observed between Iba1 microglial staining and (A) AT8 p-tau staining (T2+/+PS: n = 12, **P < 0.01, R2 = 0.6743; T2−/−PS: n = 21, **P < 0.01, R2 = 0.3392) and (B) FA-soluble htau levels (T2+/+PS: n = 12, **P < 0.01, R2 = 0.5560; T2−/−PS: n = 16, *P < 0.05, R2 = 0.2475) in both groups, but were stronger in T2+/+PS mice. Additionally, significant correlations for ventricular size and (C) AT8 p-tau staining (T2+/+PS: n = 13, *P < 0.05, R2 = 0.4312; T2−/−PS: n = 19, not significant P > 0.05, R2 = 0.0064) and (D) FA-soluble htau levels (T2+/+PS: n = 13, *P < 0.05, R2 = 0.3185; T2−/−PS: n = 14, not significant P > 0.05, R2 = 0.0114) were observed for T2+/+PS but not T2−/−PS mice. Solid, colored lines represent the best-fit line with a linear regression, and black, dashed lines represent 95% confidence intervals.
Fig. S3. Correlations between tau pathology, microgliosis, and degeneration in the hippocampus of T2+/+PS and T2−/−PS mice. Significant correlations were observed between Iba1 microglial staining and (A) AT8 p-tau staining (T2+/+PS: n = 12, **P < 0.01, R2 = 0.6743; T2−/−PS: n = 21, **P < 0.01, R2 = 0.3392) and (B) FA-soluble htau levels (T2+/+PS: n = 12, **P < 0.01, R2 = 0.5560; T2−/−PS: n = 16, *P < 0.05, R2 = 0.2475) in both groups, but were stronger in T2+/+PS mice. Additionally, significant correlations for ventricular size and (C) AT8 p-tau staining (T2+/+PS: n = 13, *P < 0.05, R2 = 0.4312; T2−/−PS: n = 19, not significant P > 0.05, R2 = 0.0064) and (D) FA-soluble htau levels (T2+/+PS: n = 13, *P < 0.05, R2 = 0.3185; T2−/−PS: n = 14, not significant P > 0.05, R2 = 0.0114) were observed for T2+/+PS but not T2−/−PS mice. Solid, colored lines represent the best-fit line with a linear regression, and black, dashed lines represent 95% confidence intervals.CC BY-NC-ND · PubMed Central
Fig. 4. Decreased microglial activation and inflammatory gene expression in T2−/−PS mice. (A) Expression of microglial homeostatic (Tmem119: P = 0.1755; and P2ry12: P = 0.6323) and activated markers in the cortex of T2+/+PS and T2−/−PS mice (Cst7: P = 0.0274; Spp1: P = 0.2256; ApoE: P = 0.0088). (B) Representative images of ApoE-positive puncta in Iba1-positive cell bodies from coimmunofluorescence staining in the piriform cortex of T2+/+PS and T2−/−PS mice. Images represent maximum-intensity projections of z stacks. (Scale bars, 50 µm.) (C) Quantification of the percentage of Iba1-positive microglial cell bodies with ApoE accumulation in the piriform cortex (P = 0.0003; T2+/+PS, n = 12; T2−/−PS, n = 20). (D) Expression of inflammatory genes in the cortex of T2+/+PS and T2−/−PS mice (IL-1α, P = 0.0021; IL-1β, P = 0.0009; TNF-α, P = 0.0133; and C1q, P = 0.0136; IL-6, P = 0.5512). n = 9–10 for all qRT-PCR analyses. All graphs represent the mean ± SEM. Significance was determined using an unpaired, two-tailed Student’s t test with “ns” denoting not significant, *P < 0.05, **P < 0.01, and ***P < 0.001.
Fig. 4. Decreased microglial activation and inflammatory gene expression in T2−/−PS mice. (A) Expression of microglial homeostatic (Tmem119: P = 0.1755; and P2ry12: P = 0.6323) and activated markers in the cortex of T2+/+PS and T2−/−PS mice (Cst7: P = 0.0274; Spp1: P = 0.2256; ApoE: P = 0.0088). (B) Representative images of ApoE-positive puncta in Iba1-positive cell bodies from coimmunofluorescence staining in the piriform cortex of T2+/+PS and T2−/−PS mice. Images represent maximum-intensity projections of z stacks. (Scale bars, 50 µm.) (C) Quantification of the percentage of Iba1-positive microglial cell bodies with ApoE accumulation in the piriform cortex (P = 0.0003; T2+/+PS, n = 12; T2−/−PS, n = 20). (D) Expression of inflammatory genes in the cortex of T2+/+PS and T2−/−PS mice (IL-1α, P = 0.0021; IL-1β, P = 0.0009; TNF-α, P = 0.0133; and C1q, P = 0.0136; IL-6, P = 0.5512). n = 9–10 for all qRT-PCR analyses. All graphs represent the mean ± SEM. Significance was determined using an unpaired, two-tailed Student’s t test with “ns” denoting not significant, *P < 0.05, **P < 0.01, and ***P < 0.001.CC BY-NC-ND · PubMed Central
Fig. 5. Reduced astrogliosis in T2−/−PS mice. (A) Expression of cortical GFAP (P = 0.0019). Quantification of the percent area covered by GFAP staining in the (B) piriform cortex (P = 0.0282; T2+/+PS, n = 14; T2−/−PS, n = 20) and (C) hippocampus (P = 0.0067; T2+/+PS, n = 14; T2−/−PS, n = 19). Representative images of GFAP immunohistochemistry in the (D) piriform cortex and (E) hippocampus of T2+/+PS and T2−/−PS mice. (Scale bars, 1 mm.) Data are mean ± SEM. Significance was determined using an unpaired, two-tailed Student’s t test with *P < 0.05 and **P < 0.01.
Fig. 5. Reduced astrogliosis in T2−/−PS mice. (A) Expression of cortical GFAP (P = 0.0019). Quantification of the percent area covered by GFAP staining in the (B) piriform cortex (P = 0.0282; T2+/+PS, n = 14; T2−/−PS, n = 20) and (C) hippocampus (P = 0.0067; T2+/+PS, n = 14; T2−/−PS, n = 19). Representative images of GFAP immunohistochemistry in the (D) piriform cortex and (E) hippocampus of T2+/+PS and T2−/−PS mice. (Scale bars, 1 mm.) Data are mean ± SEM. Significance was determined using an unpaired, two-tailed Student’s t test with *P < 0.05 and **P < 0.01.CC BY-NC-ND · PubMed Central
Fig. S4. Correlations between astrogliosis, tau pathology, and microgliosis in the hippocampus of T2+/+PS and T2−/−PS mice. Strong, significant correlations were observed between GFAP staining and (A) AT8 p-tau staining (T2+/+PS: n = 12, **P < 0.01, R2 = 0.5130; T2−/−PS: n = 19, ***P < 0.001, R2 = 0.6311) for both T2+/+PS and T2−/−PS mice. (B) Correlations between GFAP and Iba1 were reduced in T2−/−PS compared with T2+/+PS mice (T2+/+PS: n = 13, **P < 0.01, R2 = 0.5610; T2−/−PS: n = 19, *P < 0.05, R2 = 0.2430). Solid, colored lines represent the best-fit line with a linear regression, and black, dashed lines represent 95% confidence intervals.
Fig. S4. Correlations between astrogliosis, tau pathology, and microgliosis in the hippocampus of T2+/+PS and T2−/−PS mice. Strong, significant correlations were observed between GFAP staining and (A) AT8 p-tau staining (T2+/+PS: n = 12, **P < 0.01, R2 = 0.5130; T2−/−PS: n = 19, ***P < 0.001, R2 = 0.6311) for both T2+/+PS and T2−/−PS mice. (B) Correlations between GFAP and Iba1 were reduced in T2−/−PS compared with T2+/+PS mice (T2+/+PS: n = 13, **P < 0.01, R2 = 0.5610; T2−/−PS: n = 19, *P < 0.05, R2 = 0.2430). Solid, colored lines represent the best-fit line with a linear regression, and black, dashed lines represent 95% confidence intervals.CC BY-NC-ND · PubMed Central

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Authors
Leyns, C. E. G., Ulrich, J. D., Finn, M. B., Stewart, F. R., Koscal, L. J., Remolina Serrano, J., Robinson, G. O., Anderson, E., Colonna, M., & Holtzman, D. M.
Affiliations
  • Washington University in St. Louis (US)
  • Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110;
Corresponding author
Holtzman, David M.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2017-10-09
Volume
114
Issue
43
Pages
11524-11529
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1710311114
PMC
PMC5663386
OpenAlex
W2763928642
Cited by
517
References
50
Citations by year
2026: 41 · 2025: 51 · 2024: 55 · 2023: 78 · 2022: 79 · 2021: 69 · 2020: 54 · 2019: 44 · 2018: 42 · 2017: 3
FWCI
19.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
Funders
  • Cure Alzheimer's Fund
  • Hope Center for Neurological Disorders
  • Center for Cellular Imaging, Washington University
  • National Institute on Aging (F31AG053976)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
TREM2, tauopathy, neuroinflammation, neurodegeneration, Alzheimer's disease, microglia, tau pathology, brain atrophy, amyloid-beta, TREM2 deficiency, mouse model
MeSH terms
Animals, Gene Expression Regulation, Inflammation, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Mice, Knockout, Neurodegenerative Diseases, Tauopathies, Mice

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