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Cited by 232Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

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Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy

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Sayed, Faten A., Telpoukhovskaia, Maria, Kodama, Lay, Li, Yaqiao, Zhou, Yungui, Le, David, Hauduc, Axel, Ludwig, Connor, Gao, Fuying, Clelland, Claire, Zhan, Lihong, Cooper, Yonatan A., Davalos, Dimitrios, Akassoglou, Katerina, Coppola, Giovanni, Gan, Li·2018·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1811411115PMC PMC6176614
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Abstract

Alzheimer’s disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 ( TREM2 ) are associated with elevated risk for developing late-onset AD. These variants are hypothesized to result in loss of function, mimicking TREM2 haploinsufficiency. However, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report the effects of partial and complete loss of TREM2 on microglial function and tau-associated deficits. In vivo imaging revealed that microglia from aged TREM2-haploinsufficient mice show a greater impairment in their injury response compared with microglia from aged TREM2-KO mice. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. In addition, whereas complete TREM2 deficiency protected against tau-mediated microglial activation and atrophy, TREM2 haploinsufficiency elevated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathology provide important insights into the critical role of TREM2 in AD pathogenesis.

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Fig. 1. TREM2 haploinsufficiency causes an age-dependent impairment of microglia’s injury response in vivo. (A–E) Quantification of microglial motility in 3–5-mo-old mice. Quantification of the average speed per microglial process (A) and total change in length of microglial processes (B) during 10-min baseline recordings from 3–5-mo-old mice. TREM2+/+, n = 7 recordings from 7 mice; TREM2+/−, n = 9 recordings from 9 mice; TREM2−/−, n = 10 recordings from 10 mice. (C) Microglial density for young mice from laser-induced tissue injury videos. TREM2+/+, n = 10 recordings from 9 mice; TREM2+/−, n = 11 recordings from 10 mice; TREM2−/−, n = 12 recordings from 10 mice. (D) Representative still images at 3 min, 21 min, 39 min, and 57 min from the microglial responses to injury in young mice. Laser ablations are outlined with smaller white circles. The response was normalized to microglial density at each time point, denoted by larger white circles. (Scale bar: 20 μm.) (E) Quantification of normalized microglial responses from young mice toward focal laser-induced tissue injury over a period of 60 min from time of injury. TREM2+/+, n = 7 injuries from 7 mice; TREM2+/−, n = 11 injuries from 10 mice; TREM2−/−, n = 12 injuries from 10 mice. (F–H) Quantification of microglial motility in 9–14-mo old mice. (F) Quantification of the average speed per microglial process and (G) total change in length of processes during 10-min baseline recordings from 9–14-mo-old mice. TREM2+/+, n = 10 recordings from 7 mice; TREM2+/−, n = 10 recordings from 9 mice; TREM2−/−, n = 10 recordings from 9 mice. (H) Microglial density for aged mice during laser-induced tissue injury experiments. TREM2+/+, n = 7 recordings from 6 mice; TREM2+/−, n = 13 recordings from 10 mice; TREM2−/−, n = 12 recordings from 9 mice. (I) Representative still images at 3 min, 21 min, 39 min, and 57 min from the microglial responses to injury in aged mice. Laser ablations are outlined with smaller white circles. Response size was normalized to microglial density at each time point, denoted by larger white circles. (Scale bar: 20 μm.) (J) Quantification of normalized microglial responses from aged mice toward focal laser-induced tissue injury was measured over a period of 60 min from time of injury. TREM2+/+, n = 6 injuries from 5 mice; TREM2+/−, n = 13 injuries from 10 mice; TREM2−/−, n = 12 injuries from 9 mice (****P < 0.0001, STATA mixed-effects modeling). Values are expressed as mean ± SEM. Data were analyzed using one-way ANOVA with Bonferroni post hoc analyses for all panels except for E and J, which were analyzed by using STATA mixed-effects modeling.
Fig. 1. TREM2 haploinsufficiency causes an age-dependent impairment of microglia’s injury response in vivo. (A–E) Quantification of microglial motility in 3–5-mo-old mice. Quantification of the average speed per microglial process (A) and total change in length of microglial processes (B) during 10-min baseline recordings from 3–5-mo-old mice. TREM2+/+, n = 7 recordings from 7 mice; TREM2+/−, n = 9 recordings from 9 mice; TREM2−/−, n = 10 recordings from 10 mice. (C) Microglial density for young mice from laser-induced tissue injury videos. TREM2+/+, n = 10 recordings from 9 mice; TREM2+/−, n = 11 recordings from 10 mice; TREM2−/−, n = 12 recordings from 10 mice. (D) Representative still images at 3 min, 21 min, 39 min, and 57 min from the microglial responses to injury in young mice. Laser ablations are outlined with smaller white circles. The response was normalized to microglial density at each time point, denoted by larger white circles. (Scale bar: 20 μm.) (E) Quantification of normalized microglial responses from young mice toward focal laser-induced tissue injury over a period of 60 min from time of injury. TREM2+/+, n = 7 injuries from 7 mice; TREM2+/−, n = 11 injuries from 10 mice; TREM2−/−, n = 12 injuries from 10 mice. (F–H) Quantification of microglial motility in 9–14-mo old mice. (F) Quantification of the average speed per microglial process and (G) total change in length of processes during 10-min baseline recordings from 9–14-mo-old mice. TREM2+/+, n = 10 recordings from 7 mice; TREM2+/−, n = 10 recordings from 9 mice; TREM2−/−, n = 10 recordings from 9 mice. (H) Microglial density for aged mice during laser-induced tissue injury experiments. TREM2+/+, n = 7 recordings from 6 mice; TREM2+/−, n = 13 recordings from 10 mice; TREM2−/−, n = 12 recordings from 9 mice. (I) Representative still images at 3 min, 21 min, 39 min, and 57 min from the microglial responses to injury in aged mice. Laser ablations are outlined with smaller white circles. Response size was normalized to microglial density at each time point, denoted by larger white circles. (Scale bar: 20 μm.) (J) Quantification of normalized microglial responses from aged mice toward focal laser-induced tissue injury was measured over a period of 60 min from time of injury. TREM2+/+, n = 6 injuries from 5 mice; TREM2+/−, n = 13 injuries from 10 mice; TREM2−/−, n = 12 injuries from 9 mice (****P < 0.0001, STATA mixed-effects modeling). Values are expressed as mean ± SEM. Data were analyzed using one-way ANOVA with Bonferroni post hoc analyses for all panels except for E and J, which were analyzed by using STATA mixed-effects modeling.CC BY-NC-ND · PubMed Central
Fig. 2. Differential effects of partial and complete loss of TREM2 on the microglial transcriptome. (A) RNA-seq of microglia isolated from the forebrain of 3–4-mo-old mice (TREM2+/+, n = 4 samples from 8 mice; TREM2+/−, n = 3 samples from 6 mice; TREM2−/−, n = 3 samples from 6 mice). Expression levels of the top 100 most enriched transcripts in astrocytes (AS), endothelial cells (EN), microglia (MG), neurons (NE), and oligodendrocytes (OG), as identified by Zhang et al. (27). Columns 1–5: data from Zhang et al. Columns 6–15: expression data in microglia from TREM2+/+, TREM2+/−, and TREM2−/− mice. Shades of red correspond to increased levels compared with average gene expression, and shades of blue correspond to decreased levels. (B) Heat map representing significantly altered transcripts (P < 0.005) across all genotypes. Samples are in columns and genes are in rows. Shades of red represent up-reglation, and shades of green represent down-regulation. (C) Venn diagram illustrating the number and overlap of transcripts that were significantly altered between the two indicated genotypes (P < 0.005). (D) IPA of top six enriched disease and biological function pathways from 107 transcripts that were significantly altered in TREM2−/− microglia compared with TREM2+/− microglia (P < 0.005). Bars indicate −log (P value) of enrichment. Red dotted line corresponds to P = 0.05.
Fig. 2. Differential effects of partial and complete loss of TREM2 on the microglial transcriptome. (A) RNA-seq of microglia isolated from the forebrain of 3–4-mo-old mice (TREM2+/+, n = 4 samples from 8 mice; TREM2+/−, n = 3 samples from 6 mice; TREM2−/−, n = 3 samples from 6 mice). Expression levels of the top 100 most enriched transcripts in astrocytes (AS), endothelial cells (EN), microglia (MG), neurons (NE), and oligodendrocytes (OG), as identified by Zhang et al. (27). Columns 1–5: data from Zhang et al. Columns 6–15: expression data in microglia from TREM2+/+, TREM2+/−, and TREM2−/− mice. Shades of red correspond to increased levels compared with average gene expression, and shades of blue correspond to decreased levels. (B) Heat map representing significantly altered transcripts (P < 0.005) across all genotypes. Samples are in columns and genes are in rows. Shades of red represent up-reglation, and shades of green represent down-regulation. (C) Venn diagram illustrating the number and overlap of transcripts that were significantly altered between the two indicated genotypes (P < 0.005). (D) IPA of top six enriched disease and biological function pathways from 107 transcripts that were significantly altered in TREM2−/− microglia compared with TREM2+/− microglia (P < 0.005). Bars indicate −log (P value) of enrichment. Red dotted line corresponds to P = 0.05.CC BY-NC-ND · PubMed Central
Fig. 3. Differential effects of partial and complete loss of TREM2 on P301S-induced transcriptional changes. (A) Venn diagram illustrating the number and overlap of transcripts that were significantly altered between the two indicated P301S+ genotypes from 8–9-mo-old mice (P < 0.005, four mice per genotype, one mouse per sample). (B) Gene Set Enrichment Analysis (GSEA) using the hallmark database on significantly differentially expressed transcripts between partial vs. complete loss of TREM2 in P301S mice. The top 10 most enriched pathways are shown. The fraction on the bar graph indicates the total number of genes curated in the database for the specified term (denominator) and the number of overlapping genes in the inputted RNA-seq dataset (numerator).
Fig. 3. Differential effects of partial and complete loss of TREM2 on P301S-induced transcriptional changes. (A) Venn diagram illustrating the number and overlap of transcripts that were significantly altered between the two indicated P301S+ genotypes from 8–9-mo-old mice (P < 0.005, four mice per genotype, one mouse per sample). (B) Gene Set Enrichment Analysis (GSEA) using the hallmark database on significantly differentially expressed transcripts between partial vs. complete loss of TREM2 in P301S mice. The top 10 most enriched pathways are shown. The fraction on the bar graph indicates the total number of genes curated in the database for the specified term (denominator) and the number of overlapping genes in the inputted RNA-seq dataset (numerator).CC BY-NC-ND · PubMed Central
Fig. 4. TREM2 haploinsufficiency exacerbates tau pathology in P301S+ mice. (A) Representative images of AT8 immunostaining in the cortex of 8–9-mo-old mice. (Scale bar: 100 μm.) (B) Quantification of the percentage of AT8+ area in the cortex of P301S+ TREM2+/+, n = 9 mice; P301S+ TREM2+/−, n = 25 mice; P301S+ TREM2−/−, n = 9 mice; 6–8 sections per mouse (*P < 0.05, STATA mixed-effects modeling). (C) Representative images of AT8 immunostaining in the hippocampus of 8–9-mo-old mice. (Scale bar: 300 μm.) (D) Quantification of the percentage of AT8+ area in the hippocampus of P301S+ TREM2+/+, n = 9 mice; P301S+ TREM2+/−, n = 25 mice; P301S+ TREM2−/−, n = 10 mice; 6–8 sections per mouse. (E) Representative images of MC1 immunostaining in the cortex of 8–9-mo-old mice. (Scale bar: 300 μm.) (F) Quantification of the percentage of MC1+ area in the cortex of P301S+ TREM2+/+, n = 9 mice; P301S+ TREM2+/−, n = 25 mice; P301S+ TREM2−/−, n = 9 mice; 7–16 sections per mouse (**P < 0.01, R mixed-effects modeling). (G) Representative images of MC1 immunostaining in the hippocampus of 8–9-mo-old mice. (Scale bar: 100 μm.) (H) Quantification of the percentage of MC1+ area in the hippocampus of P301S+ TREM2+/+, n = 9 mice; P301S+ TREM2+/−, n = 25 mice; P301S+ TREM2−/−, n = 10 mice; 7–16 sections/mouse (**P < 0.01, ***P < 0.001, R mixed-effects modeling). Values are expressed as mean ± SEM.
Fig. 4. TREM2 haploinsufficiency exacerbates tau pathology in P301S+ mice. (A) Representative images of AT8 immunostaining in the cortex of 8–9-mo-old mice. (Scale bar: 100 μm.) (B) Quantification of the percentage of AT8+ area in the cortex of P301S+ TREM2+/+, n = 9 mice; P301S+ TREM2+/−, n = 25 mice; P301S+ TREM2−/−, n = 9 mice; 6–8 sections per mouse (*P < 0.05, STATA mixed-effects modeling). (C) Representative images of AT8 immunostaining in the hippocampus of 8–9-mo-old mice. (Scale bar: 300 μm.) (D) Quantification of the percentage of AT8+ area in the hippocampus of P301S+ TREM2+/+, n = 9 mice; P301S+ TREM2+/−, n = 25 mice; P301S+ TREM2−/−, n = 10 mice; 6–8 sections per mouse. (E) Representative images of MC1 immunostaining in the cortex of 8–9-mo-old mice. (Scale bar: 300 μm.) (F) Quantification of the percentage of MC1+ area in the cortex of P301S+ TREM2+/+, n = 9 mice; P301S+ TREM2+/−, n = 25 mice; P301S+ TREM2−/−, n = 9 mice; 7–16 sections per mouse (**P < 0.01, R mixed-effects modeling). (G) Representative images of MC1 immunostaining in the hippocampus of 8–9-mo-old mice. (Scale bar: 100 μm.) (H) Quantification of the percentage of MC1+ area in the hippocampus of P301S+ TREM2+/+, n = 9 mice; P301S+ TREM2+/−, n = 25 mice; P301S+ TREM2−/−, n = 10 mice; 7–16 sections/mouse (**P < 0.01, ***P < 0.001, R mixed-effects modeling). Values are expressed as mean ± SEM.CC BY-NC-ND · PubMed Central
Fig. 5. Differential effects of partial and complete loss of TREM2 on atrophy in P301S+ mice. (A) Representative images of NeuN immunostaining from 8–9-mo-old mice. Lateral ventricle outlined with a white dashed line. (B) Quantification of the lateral ventricle area of TREM2+/+, n = 6 mice; P301S+ TREM2+/+, n = 9 mice; P301S+ TREM2+/−, n = 25 mice; P301S+ TREM2−/−, n = 10 mice, 6–17 sections per mouse (*P < 0.05, one-way ANOVA with Bonferroni post hoc analysis). (C) Quantification of the hippocampal area in 8–9-mo-old TREM2+/+, n = 6; P301S+ TREM2+/+, n = 9; P301S+ TREM2+/−, n = 25; and P301S+ TREM2−/−, n = 10 mice, 6–17 sections per mouse. (D) Representative images of NeuN immunostaining from 10–11-mo-old mice. Lateral ventricle outlined with a white dashed line. (E) Quantification of the lateral ventricle area of TREM2+/+, n = 12 mice; P301S+ TREM2+/+, n = 12 mice; P301S+ TREM2+/−, n = 11 mice; n = 6–8 sections per mouse (***P < 0.001, one-way ANOVA with Bonferroni post hoc analysis). Values are expressed as mean ± SEM.
Fig. 5. Differential effects of partial and complete loss of TREM2 on atrophy in P301S+ mice. (A) Representative images of NeuN immunostaining from 8–9-mo-old mice. Lateral ventricle outlined with a white dashed line. (B) Quantification of the lateral ventricle area of TREM2+/+, n = 6 mice; P301S+ TREM2+/+, n = 9 mice; P301S+ TREM2+/−, n = 25 mice; P301S+ TREM2−/−, n = 10 mice, 6–17 sections per mouse (*P < 0.05, one-way ANOVA with Bonferroni post hoc analysis). (C) Quantification of the hippocampal area in 8–9-mo-old TREM2+/+, n = 6; P301S+ TREM2+/+, n = 9; P301S+ TREM2+/−, n = 25; and P301S+ TREM2−/−, n = 10 mice, 6–17 sections per mouse. (D) Representative images of NeuN immunostaining from 10–11-mo-old mice. Lateral ventricle outlined with a white dashed line. (E) Quantification of the lateral ventricle area of TREM2+/+, n = 12 mice; P301S+ TREM2+/+, n = 12 mice; P301S+ TREM2+/−, n = 11 mice; n = 6–8 sections per mouse (***P < 0.001, one-way ANOVA with Bonferroni post hoc analysis). Values are expressed as mean ± SEM.CC BY-NC-ND · PubMed Central
Fig. 6. Differential regulation of inflammation by partial and complete loss of TREM2 in P301S+ mice. (A) Representative images of Iba1 immunostaining of microglia in the hippocampus of 8–9-mo-old mice. (Scale bar: 300 μm.) (B) Quantification of the number of microglia per millimeter squared in the hippocampus of TREM2+/+, n = 5 mice; P301S+ TREM2+/+, n = 9 mice; P301S+ TREM2+/−, n = 25 mice; P301S+ TREM2−/−, n = 10 mice; 6–17 sections per mouse (*P < 0.05, R mixed-effects modeling). (C) Significant positive correlation between hippocampal percent MC1+ area and number of Iba1+ cells per square millimeter (***P < 0.001, linear regression). Each dot represents one animal. Graph depicts mean and 95% CIs. Genotypes are color-coded according to key. (D) Representative images of hippocampal Iba1 immunostaining and the corresponding 3D reconstructions using Imaris. (Scale bars: full-view images, 40 μm; magnified images, 20 μm.) (E) Quantification of the length sum of microglial processes and (F) number of microglial branches in TREM2+/+, n = 4 mice (35 cells); P301S+ TREM2+/+, n = 7 mice (123 cells); P301S+ TREM2+/−, n = 9 mice (169 cells); P301S+ TREM2−/−, n = 5 mice (64 cells; *P < 0.05 and ***P < 0.001, one-way ANOVA with Bonferroni post hoc analysis). Values are expressed as mean ± SEM.
Fig. 6. Differential regulation of inflammation by partial and complete loss of TREM2 in P301S+ mice. (A) Representative images of Iba1 immunostaining of microglia in the hippocampus of 8–9-mo-old mice. (Scale bar: 300 μm.) (B) Quantification of the number of microglia per millimeter squared in the hippocampus of TREM2+/+, n = 5 mice; P301S+ TREM2+/+, n = 9 mice; P301S+ TREM2+/−, n = 25 mice; P301S+ TREM2−/−, n = 10 mice; 6–17 sections per mouse (*P < 0.05, R mixed-effects modeling). (C) Significant positive correlation between hippocampal percent MC1+ area and number of Iba1+ cells per square millimeter (***P < 0.001, linear regression). Each dot represents one animal. Graph depicts mean and 95% CIs. Genotypes are color-coded according to key. (D) Representative images of hippocampal Iba1 immunostaining and the corresponding 3D reconstructions using Imaris. (Scale bars: full-view images, 40 μm; magnified images, 20 μm.) (E) Quantification of the length sum of microglial processes and (F) number of microglial branches in TREM2+/+, n = 4 mice (35 cells); P301S+ TREM2+/+, n = 7 mice (123 cells); P301S+ TREM2+/−, n = 9 mice (169 cells); P301S+ TREM2−/−, n = 5 mice (64 cells; *P < 0.05 and ***P < 0.001, one-way ANOVA with Bonferroni post hoc analysis). Values are expressed as mean ± SEM.CC BY-NC-ND · PubMed Central

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Authors
Sayed, F. A., Telpoukhovskaia, M., Kodama, L., Li, Y., Zhou, Y., Le, D., Hauduc, A., Ludwig, C., Gao, F., Clelland, C., Zhan, L., Cooper, Y. A., Davalos, D., Akassoglou, K., Coppola, G., & Gan, L.
Affiliations
  • Gladstone Institutes (US)
  • University of California, Los Angeles (US)
Corresponding author
Gan, Li
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2018-09-19
Volume
115
Issue
40
Pages
10172-10177
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1811411115
PMC
PMC6176614
OpenAlex
W2890556232
Cited by
229
References
35
Citations by year
2026: 15 · 2025: 23 · 2024: 31 · 2023: 40 · 2022: 44 · 2021: 33 · 2020: 19 · 2019: 21 · 2018: 3
FWCI
8.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders
HHS | NIH | National Institute on Aging (R01AG051390, R01AG054214)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
TREM2, Alzheimer's disease, tauopathy, microglial activation, TREM2 knockout mice, pro-inflammatory markers
MeSH terms
Aging, Alzheimer Disease, Animals, Membrane Glycoproteins, Receptors, Immunologic, Microglia, Mice, Knockout, Mutation, Missense, Mice, Haploinsufficiency, Hemizygote

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