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Cited by 83Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease

Open access
Bonham, Luke W., Sirkis, Daniel W., Yokoyama, Jennifer S.·2019·Frontiers in Immunology
DOI 10.3389/fimmu.2019.01170PMC PMC6557985
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Abstract

Microglia, the brain-resident myeloid cells, are strongly implicated in Alzheimer’s disease (AD) pathogenesis by human genetics. However, the mechanisms by which microglial gene expression is regulated in a region-specific manner over the course of normal aging and in neurodegenerative disease are only beginning to be deciphered. Herein, we used a specific marker of microglia (TMEM119) and a cell-type expression profiling tool (CellMapper) to identify a human microglial gene expression module. Surprisingly, we found that microglial module genes are robustly expressed in several healthy human brain regions known to be vulnerable in AD, in addition to other regions affected only later in disease or spared in AD. Surveying the microglial gene set for differential expression over the lifespan in mouse models of AD and a related tauopathy revealed that the majority of microglial module genes were significantly upregulated in cortex and hippocampus as a function of age and transgene status. Extending these results, we also observed significant upregulation of microglial module genes in several AD-affected brain regions in addition to other regions using postmortem brain tissue from human AD samples. In pathologically confirmed AD cases, we found preliminary evidence that microglial genes may be dysregulated in a sex-specific manner. Finally, we identified specific and significant overlap between the described microglial gene set—identified by unbiased co-expression analysis—and genes known to impart risk for AD. Our findings suggest that microglial genes show enriched expression in AD-vulnerable brain regions, are upregulated during aging and neurodegeneration in mice, and are upregulated in pathologically affected brain regions in AD. Taken together, our data-driven findings from multiple publicly accessible datasets reemphasize the importance of microglial gene expression alterations in AD and, more importantly, suggest that regional and sex-specific variation in microglial gene expression may be implicated in risk for and progression of neurodegenerative disease.

AI snapshot

Written from the paper’s full text.

TL;DR

Using TMEM119 and CellMapper, the authors derived a 30-gene human microglial expression module and found it enriched in several AD-vulnerable brain regions, upregulated with age and transgene status in mouse models, and upregulated in AD-affected human brain regions. The module also showed AD-specific genetic enrichment and preliminary sex-specific dysregulation in pathologically confirmed AD.

Key findings

  • CellMapper with TMEM119 identified 30 microglial genes at pFDR < 0.05; 11 remained significant at pFDR < 0.01 (IGSF6, ADORA3, ALOX5AP, CSF2RA, HPGDS, P2RY13, ACY3, SUSD3, SASH3, TBXAS1, RASAL3).
  • In healthy human brain, microglial genes were significantly enriched in 48 of 194 testable regions at pFDR < 0.05, including parietal cortex, temporal cortex regions, basal ganglia, and brainstem nuclei; cerebellum and occipital cortex showed minimal enrichment.
  • In mouse models, 16/20 orthologous microglial genes differed by brain region in TASTPM and 14/20 in P301L; age effects were seen for 15/20 genes, and transgene-status effects for 15/20 in TASTPM and 6/20 in P301L.
  • In human AD tissue from 584 individuals, microglial genes were upregulated in superior temporal cortex (22/24 genes), parahippocampal gyrus (19/24), inferior frontal gyrus (14/24), and temporal cortex (13/26), with fewer changes in frontal pole (1/24) and DLPFC (3/21); AD was the only disease enriched among >3,000 traits in FUMA (raw p = 8.87 × 10−6; FDR p = 0.017).

Methods

  • Microglial genes were identified using CellMapper with TMEM119 in bulk human brain data from the Allen Brain Institute (6 adult control samples), then tested for regional enrichment using bootstrapping and FDR correction.
  • Mouse analyses used Mouseac microarray data from TASTPM and P301L transgenic models versus wild type at 8, 16, 32, and 72 weeks across cortex, hippocampus, and cerebellum; ANOVA used a Bonferroni threshold of p = 0.000357.
  • Human AD analyses used RNAseq from AMP-AD MSSM, Mayo, and ROSMAP cohorts (over 500 individuals; 584 in combined analyses), with linear regression controlling for sex, age, postmortem interval, and technical confounders; FUMA hypergeometric testing assessed AD risk-gene enrichment.

Limitations

  • The paper states that bulk tissue cannot distinguish increased microglial density from altered microglial transcription, and that scRNAseq data from finely dissected human brain regions showing upregulation were not available.
  • The authors state that pooling multiple public cohorts required batch-effect and covariate correction and still could not fully disentangle whether findings were AD-specific, driven by microglial density, or both; some relevant regions were unavailable.
  • The authors note mouse models carry familial mutations and may not reflect sporadic disease, TASTPM lacks neurofibrillary tangles, and CellMapper was designed for microarray data and requires validated, highly specific cell markers; sex-specific findings were described as preliminary with modest effect size.

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

Integrity signals

Registry

Crossref · 10.3389/fimmu.2019.01170

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 60 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    With a stricter significance threshold of pFDR < 0.01, 11 of the microglial genes remained significant: IGSF6, ADORA3, ALOX5AP, CSF2RA, HPGDS, P2RY13, ACY3, SUSD3, SASH3, TBXAS1, and RASAL3.

    “Using a stricter significance threshold of pFDR < 0.01, 11 genes remained significant (IGSF6, ADORA3, ALOX5AP, CSF2RA, HPGDS, P2RY13, ACY3, SUSD3, SASH3, TBXAS1, and RASAL3).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The described microglial gene set, identified by unbiased co-expression analysis, shows specific and significant overlap with genes known to impart risk for AD.

    “Finally, we identified specific and significant overlap between the described microglial gene set—identified by unbiased co-expression analysis—and genes known to impart risk for AD.”
    Quote in the paperSubstantial claim
  • Findingown data

    In mouse models of AD and a related tauopathy, the majority of microglial module genes were significantly upregulated in cortex and hippocampus as a function of age and transgene status.

    “Surveying the microglial gene set for differential expression over the lifespan in mouse models of AD and a related tauopathy revealed that the majority of microglial module genes were significantly upregulated in cortex and hippocampus as a function of age and transgene status.”
    Quote in the paperSubstantial claim
  • Findingown data

    In healthy human brain tissue, the microglial gene set showed significant enrichment in 48 out of 194 testable brain regions at pFDR < 0.05.

    “Our analyses revealed significant enrichment in 48 out of 194 testable brain regions at a pFDR < 0.05 (Table 4, Figure 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    Microglial gene enrichment in healthy human brain is particularly notable in the parietal cortex, areas of the temporal cortex (e.g., temporal pole, parahippocampal gyrus, amygdalohippocampal transition), basal ganglia (e.g., putamen and globus pallidus), and brainstem nuclei (e.g., vestibular nuclei, pontine nuclei, and paraventricular nuclei).

    “Of note, enrichment was particularly notable in the parietal cortex, areas of the temporal cortex (e.g., temporal pole, parahippocampal gyrus, amygdalohippocampal transition), basal ganglia (e.g., putamen and globus pallidus), and brainstem nuclei (e.g., vestibular nuclei, pontine nuclei, and paraventricular nuclei) (Table 4, Figure 1).”
    Quote in the paperSubstantial claim
  • May combine two claims. 36
  • Classified as probably not a substantial claim. 27

  • May combine two claims.

    Findingown data

    In healthy human brain, the frontal lobes showed comparably less microglial gene enrichment relative to other brain regions, but there was significant enrichment in the inferior frontal gyrus and frontal pole.

    “Although the frontal lobes showed comparably less enrichment relative to other brain regions, there was significant enrichment in the inferior frontal gyrus and frontal pole.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The cerebellum showed mixed associations, with 13 of 26 genes upregulated and others showing no apparent changes in AD.

    “Interestingly, the cerebellum showed mixed associations, with 13 of 26 genes upregulated and others showing no apparent changes in AD (Figure S2) despite being a region that is usually spared from atrophy in early AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the P301L model, significant interactions were observed for transgene status by age (16/20) and transgene status by age and region (14/20), but not transgene status by region (0/20).

    “Similar results were observed in the P301L model, with significant interactions for transgene status by age (16/20) and transgene status by age and region (14/20), but not transgene status by region (0/20) (Table 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The main effect of age was important in the combined TASTPM and WT mouse data as well as the P301L and WT mouse cohorts, with 15/20 microglial genes (75%) showing differential expression.

    “Similarly, the main effect of age was important in the combined TASTPM and WT mouse data as well as the P301L and WT mouse cohorts with 15/20 microglial genes (75%), inclusive of the ones observed in the other two models, showing differential expression (Tables 5, 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For transgene status by age and region analyses, the two additional genes identified in P301L that were not identified in TASTPM were Alox5ap and Cd33, both close to the significance cutoff (p = 0.000357).

    “For the transgene status by age and region analyses, the two additional genes identified in the P301L tau model that were not identified in the TASTPM mouse were Alox5ap and Cd33—both of which were close to the significance cutoff (p = 0.000357).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The 30 microglial genes identified using cell-type profiling showed a tropism for specific brain regions, with diffuse involvement of multiple brain regions and focal involvement of specific regions such as the frontal pole, temporal cortex, basal ganglia, parietal cortex, and brain stem nuclei.

    “Our analyses suggest that there is diffuse involvement of multiple brain regions, but also that there is focal involvement of specific regions such as the frontal pole, temporal cortex, basal ganglia, parietal cortex, and brain stem nuclei.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Microglial gene expression is higher in diseased mice relative to wild-type and is upregulated in hippocampus and cortex compared to cerebellum.

    “demonstrating that microglial gene expression is higher in diseased mice relative to wild-type and is upregulated in hippocampus and cortex compared to cerebellum.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Comparing AD cases vs. controls, microglial genes are highly upregulated with significant expression differences (p < 0.05) in inferior frontal gyrus (14 of 24 genes).

    “inferior frontal gyrus (14 of 24 genes)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A steady increase in microglial gene expression with aging is evident in both wild-type and transgenic mice, but is especially prominent in the TASTPM and P301L mouse models of neurodegenerative disease.

    “Finally, a steady increase in microglial gene expression with aging is evident in both wild-type and transgenic mice, but is especially prominent in the TASTPM and P301L mouse models of neurodegenerative disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Comparing AD cases vs. controls, microglial genes are highly upregulated with significant expression differences (p < 0.05) in bulk temporal cortex (13 of 26 genes).

    “and bulk temporal cortex (13 of 26 genes)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Comparing AD cases vs. controls, microglial genes are highly upregulated with significant expression differences (p < 0.05) in superior temporal cortex (22 of 24 genes).

    “we found that microglial genes are highly upregulated, showing significant expression differences (p < 0.05) in some regions known to demonstrate significant atrophy in AD: superior temporal cortex (22 of 24 genes)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Microglial gene expression differed by sex amongst those diagnosed with AD, with significant upregulation in cerebellum (12 of 26 genes in females and 5 of 26 genes in males).

    “and cerebellum (12 of 26 genes in females and 5 of 26 genes in males)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Comparing AD cases vs. controls, microglial genes are highly upregulated with significant expression differences (p < 0.05) in parahippocampal gyrus (19 of 24 genes).

    “parahippocampal gyrus (19 of 24 genes)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the TASTPM model, significant interactions were observed for transgene status by age (15/20), transgene status by region (13/20), and transgene status by age and region (12/20).

    “In the TASTPM model, we observed significant interactions for transgene status by age (15/20), transgene status by region (13/20), and transgene status by age and region (12/20) (Table 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    With respect to transgene status by age analyses, the genes identified in each mouse model were almost identical, with exceptions being Fvb in TASTPM and Acy3 as well as Sucnr1 in P301L.

    “With respect to the transgene status by age analyses, the genes identified in each mouse model were almost identical, with the exceptions being Fvb in the TASTPM model and Acy3 as well as Sucnr1 in the P301L model.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Microglial gene expression differed by sex amongst those diagnosed with AD, with a subtle effect of increased expression in regions most impacted in AD specific to females, including significant upregulation in bulk temporal cortex (12 of 26 genes in females and 2 of 26 genes in males).

    “Our analyses suggested a subtle effect of increased expression of microglial genes in the regions most impacted in AD specific to females with significant (p < 0.05) upregulation in bulk temporal cortex (12 of 26 genes in females and 2 of 26 genes in males)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    We then surveyed the microglial gene expression module in pathologically confirmed human AD cases and found striking upregulation of the microglial module in regions impacted early in the course of AD (e.g., superior temporal cortex, parahippocampal gyrus, and inferior frontal gyrus), and somewhat less robust upregulation in the cerebellum, which is largely unaffected in AD.

    “We then surveyed the microglial gene expression module in pathologically confirmed human AD cases and found striking upregulation of the microglial module in regions impacted early in the course of AD (e.g., superior temporal cortex, parahippocampal gyrus, and inferior frontal gyrus), and somewhat less robust upregulation in the cerebellum, which is largely unaffected in AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Analysis of orthologous members of this microglial gene set in mouse models of AD and tauopathy revealed striking variation in expression level that was dictated by brain region, age, and transgene status, with highest expression observed in the aged cortex and hippocampus of mouse models of neurodegenerative disease.

    “Analysis of orthologous members of this microglial gene set in mouse models of AD and tauopathy revealed striking variation in expression level that was dictated by brain region, age, and transgene status, with highest expression observed in the aged cortex and hippocampus of mouse models of neurodegenerative disease.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    Multiple testing correction was conducted using the FDR technique.

    “Multiple testing correction was conducted using the FDR technique (15).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Benjamini, 1995, Controlling the false discovery rate: a practical and powerful approach to multiple testing, J R Stat Soc Ser B. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Microglia show sex-specific differentiation and gene expression profiles in adult mice.

    “Given that AD shows a sex-specific incidence and findings indicating that microglia show sex-specific differentiation and gene expression profiles in adult mice (27–29), we also examined whether there was a statistical interaction between AD diagnosis and sex (i.e., Gene expression = Diagnosis × Sex + covariates), using the covariate selections described above.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Guneykaya, 2018, Transcriptional and translational differences of microglia from male and female brains, Cell Rep. source

      Not checked in the free run.

    • cites [28] Kang, 2018, Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau, J Exp Med source

      Not checked in the free run.

    • cites [29] Villa, 2018, Sex-specific features of microglia from adult mice, Cell Rep. source

      Not checked in the free run.

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

    Premisecitation

    The background GWAS datasets used for the FUMA analysis come from the NHGRI-EBI catalog of published genome-wide association studies, which contains over 2,500 publications and over 24,000 single nucleotide polymorphism (SNP) trait associations.

    “The background GWAS datasets used for this analysis come from the NHGRI-EBI catalog of published genome-wide association studies (https://www.ebi.ac.uk/gwas/), which contains over 2,500 publications and over 24,000 single nucleotide polymorphism (SNP) trait associations (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] MacArthur, 2017, The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog), Nucleic Acids Res source

      Not checked in the free run.

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

    Premisecitation

    Both TASTPM and P301L mouse models are known to demonstrate a proinflammatory phenotype.

    “Both mouse models are known to demonstrate a proinflammatory phenotype (17, 18).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Götz, 2001, Tau filament formation in transgenic mice expressing P301L tau, J Biol Chem. source

      Not checked in the free run.

    • cites [18] Howlett, 2008, Aß deposition and related pathology in an APP x PS1 transgenic mouse model of Alzheimer's disease, Histol Histopathol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CellMapper requires only a single cell marker and a smaller training dataset than other techniques, and enables analysis of expression data derived from bulk brain tissue samples.

    “The technique we chose, CellMapper, requires only a single cell marker and a smaller training dataset than other techniques, and enables analysis of expression data derived from bulk brain tissue samples (10).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Nelms, 2016, CellMapper: rapid and accurate inference of gene expression in difficult-to-isolate cell types, Genome Biol. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    In all analyses, the effect of diagnosis on gene expression was tested using linear regression controlling for biological factors such as sex, age, postmortem interval, and technical confounders accounting for more than 1% of variance of the principal components.

    “In all analyses, the effect of diagnosis on gene expression was tested using linear regression controlling for biological factors such as sex, age, postmortem interval, and technical confounders accounting for more than 1% of variance of the principal components.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Data from the three brain banks' collective samples was reprocessed and harmonized using a consensus toolset at the Mount Sinai Icahn School of Medicine Minerva HPC system.

    “Data from the three brain banks' collective samples was reprocessed and harmonized using a consensus toolset at the Mount Sinai Icahn School of Medicine Minerva HPC system.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Advances in cell-type expression profiling have enabled the identification of cell-type-specific gene expression profiles.

    “Beyond the identification of specific microglial markers, advances in cell-type expression profiling have enabled the identification of cell-type-specific gene expression profiles (10).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Nelms, 2016, CellMapper: rapid and accurate inference of gene expression in difficult-to-isolate cell types, Genome Biol. source

      Not checked in the free run.

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

    Study design and conductnone given

    For the TASTPM mouse data, heterozygous and homozygous mice were analyzed together, accounting for gene dosage.

    “For the TASTPM mouse data, we analyzed heterozygous and homozygous mice together, accounting for gene dosage.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    A specific class II HLA-DR haplotype, DR15, has been suggested to impart risk for both AD and MS.

    “Beyond these findings, a specific class II human leukocyte antigen (HLA)-DR haplotype, DR15, has been suggested to impart risk for both AD and MS (7, 8).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Schmidt, 2007, HLA-DR15 haplotype and multiple sclerosis: a HuGE review, Am J Epidemiol. source

      Not checked in the free run.

    • cites [8] Steele, 2017, Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: a case-control study, PLoS Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dynamic changes in our microglial gene expression module therefore likely reflect a combination of increases in microglial cellularity and activation of specific gene expression programs (e.g., microgliosis and concomitant activation of the DAM program).

    “Dynamic changes in our microglial gene expression module therefore likely reflect a combination of increases in microglial cellularity and activation of specific gene expression programs (e.g., microgliosis and concomitant activation of the DAM program).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    P2ry13 is an ADP receptor and part of the G-protein coupled receptor family-it is thought to play a role in hematopoiesis and immune function.

    “P2ry13 is an ADP receptor and part of the G-protein coupled receptor family—it is thought to play a role in hematopoiesis and immune function (97).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Rossi, 2013, Gpr171, a putative P2Y-like receptor, negatively regulates myeloid differentiation in murine hematopoietic progenitors, Exp Hematol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Familial neurodegenerative disease is rare and the pathological processes driving it may be substantially different than those driving sporadic disease.

    “Familial neurodegenerative disease is rare and the pathological processes driving it may be substantially different than those driving sporadic disease (100).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Drummond, 2017, Alzheimer's disease: experimental models and reality, Acta Neuropathol. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    We generated the microglial expression profile using microarray data from the Allen Brain Institute.

    “Although many of our secondary analyses utilized RNAseq data, we generated the microglial expression profile using microarray data from the Allen Brain Institute.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Collectively, our findings demonstrate that microglial gene expression varies greatly by brain region and as a function of age, and responds dynamically to neurodegenerative processes in pathologically affected brain regions.

    “Collectively, our findings demonstrate that microglial gene expression varies greatly by brain region and as a function of age, and responds dynamically to neurodegenerative processes in pathologically affected brain regions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Inappropriate activation of microglia may be sufficient to induce synapse loss and neurodegeneration, while homeostatic microglia can protect against neurodegeneration.

    “Thus, while microglia are clearly capable of protecting against neurodegeneration when functioning in a homeostatic manner, inappropriate activation may be sufficient to induce synapse loss and neurodegeneration.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    We do not have AD samples from globus pallidus or corpus callosum, which would enable us to test whether microglial genes showed increased expression as a function of AD in regions that show highly enriched microglial expression in healthy brain, but which are not impacted until very late in AD.

    “For instance, we do not have AD samples from globus pallidus or corpus callosum, which would enable us to test whether microglial genes showed increased expression as a function of AD in regions that show highly enriched microglial expression in healthy brain, but which are not impacted until very late in AD.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    These limitations are especially difficult to address when analyzing bulk tissue as was done in our study.

    “These limitations are especially difficult to address when analyzing bulk tissue as was done in our study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    We utilized TMEM119 as a marker of microglial expression, which was shown in 2016 to be a highly specific marker of brain-derived microglia.

    “Secondly, we utilized TMEM119 as a marker of microglial expression, which was shown in 2016 to be a highly specific marker of brain-derived microglia (9).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Bennett, 2016, New tools for studying microglia in the mouse and human CNS, Proc Natl Acad Sci USA source

      Not checked in the free run.

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

    Premisecitation

    Several publications within the last 2 years have employed scRNAseq and mass cytometry of microglia and other CNS immune cells to understand global alterations in immunological gene expression and dynamic changes in immune cell-type abundance as a function of brain anatomy, aging, and neurodegeneration.

    “Several publications within the last 2 years have begun to employ scRNAseq and mass cytometry of microglia and other CNS immune cells as ways to understand (i) global alterations in immunological gene expression and (ii) dynamic changes in immune cell-type abundance as a function of brain anatomy, aging, and neurodegeneration (87, 95, 107, 108).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [87] Keren-Shaul, 2017, A unique microglia type associated with restricting development of Alzheimer's disease, Cell source

      Not checked in the free run.

    • cites [95] Hammond, 2018, Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes, Immunity. source

      Not checked in the free run.

    • cites [107] Ajami, 2018, Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models, Nat Neurosci. source

      Not checked in the free run.

    • cites [108] Mrdjen, 2018, High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease, Immunity. source

      Not checked in the free run.

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

    Premisecitation

    The TASTPM mouse model of AD has amyloid plaques and demonstrates memory deficits, but does not show neurofibrillary tangles.

    “For instance, the TASTPM mouse model of AD has amyloid plaques and demonstrates memory deficits, but does not show neurofibrillary tangles (101).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Howlett, 2004, Cognitive correlates of Aβ deposition in male and female mice bearing amyloid precursor protein and presenilin-1 mutant transgenes, Brain Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREM2 is also a member of our gene expression module and is known to be upregulated in DAM.

    “On the other hand, TREM2 is also a member of our gene expression module and is known to be upregulated in DAM (87, 99).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [87] Keren-Shaul, 2017, A unique microglia type associated with restricting development of Alzheimer's disease, Cell source

      Not checked in the free run.

    • cites [99] Deczkowska, 2018, Disease-associated microglia: a universal immune sensor of neurodegeneration, Cell. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The mouse models we utilized harbor genetic mutations that cause familial AD and FTLD, and thus present a unique set of limitations.

    “The mouse models we utilized harbor genetic mutations that cause familial AD and FTLD, and thus present a unique set of limitations.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The function and importance of Gpr34 and its protein product remain largely undetermined, though its suspected role in detecting short chain fatty acids may implicate it in both metabolic and immune pathways.

    “The function and importance of Gpr34 and its protein product remain largely undetermined, though its suspected role in detecting short chain fatty acids may implicate it in both metabolic and immune pathways (45, 98).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Liebscher, 2011, Altered immune response in mice deficient for the G protein-coupled receptor GPR34, J Biol Chem. source

      Not checked in the free run.

    • cites [98] Kitamura, 2012, GPR34 is a receptor for lysophosphatidylserine with a fatty acid at the sn-2 position, J Biochem. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    The primary limitations of CellMapper include that it was designed to use microarray data (not yet validated using RNAseq data) and that it requires validated as well as highly specific cell markers to accurately generate a cellular expression profile.

    “The primary limitations of CellMapper include that it was designed to use microarray data (not yet validated using RNAseq data) and that it requires validated as well as highly specific cell markers to accurately generate a cellular expression profile.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Strengths of this approach are that it enabled us to build cohorts of large sample size, detect subtle disease effects, and ensure replicability of our findings.

    “Strengths of this approach are that it enabled us to build cohorts of large sample size, detect subtle disease effects, and ensure replicability of our findings”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Combining cohorts from multiple studies requires detailed and careful correction for batch effects and covariate selection but was necessary to achieve adequate statistical power.

    “Combining cohorts from multiple studies requires detailed and careful correction for batch effects and covariate selection but was necessary to achieve adequate statistical power.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Microgliosis is a known feature of AD.

    “Microgliosis is a known feature of AD [reviewed in (92, 93)]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [92] Song, 2018, The identity and function of microglia in neurodegeneration, Nat Immunol. source

      Not checked in the free run.

    • cites [93] Yeh, 2017, TREM2, microglia, and neurodegenerative diseases, Trends Mol Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Other potential explanations of the increased expression we observed include age differences at tissue collection and use of different AD mouse models.

    “Other potential explanations of the increased expression we observed include age differences at tissue collection and use of different AD mouse models.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The protocol was approved by the University of California, San Francisco Committee on Human Research.

    “The protocol was approved by the University of California, San Francisco Committee on Human Research.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    AD is one of the most common diseases of aging and shows sex-specific incidence and progression.

    “given that AD is one of the most common diseases of aging and shows sex-specific incidence and progression (113).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Snyder, 2016, Sex biology contributions to vulnerability to Alzheimer's disease: a think tank convened by the Women's Alzheimer's Research Initiative, Alzheimers Dement. source

      Not checked in the free run.

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

    Study design and conductnone given

    The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

    “The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Microglial gene expression changes with aging.

    “and that microglial gene expression changes with aging (110–112).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [110] Galatro, 2017, Transcriptomic analysis of purified human cortical microglia reveals age-associated changes, Nat Neurosci source

      Not checked in the free run.

    • cites [111] Grabert, 2016, Microglial brain region–dependent diversity and selective regional sensitivities to aging, Nat Neurosci source

      Not checked in the free run.

    • cites [112] Soreq, 2017, Major shifts in glial regional identity are a transcriptional hallmark of human brain aging, Cell Rep. source

      Not checked in the free run.

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

    Study design and conductnone given

    This study was carried out in accordance with the recommendations of University of California, San Francisco Committee on Human Research.

    “This study was carried out in accordance with the recommendations of University of California, San Francisco Committee on Human Research.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    There is a sex dimorphism in non-diseased human tissue.

    “consistent with reports from humans showing that there is a sex dimorphism in non-diseased human tissue (109)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Thion, 2018, Microbiome influences prenatal and adult microglia in a sex-specific manner, Cell. source

      Not checked in the free run.

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

    Premisecitation

    Sexually dimorphic microglial gene expression profiles have been reported in mice.

    “Another critical issue for future work will be to determine the mechanisms responsible for sexually dimorphic microglial gene expression profiles reported in mice (28, 88) and to what extent they apply to human microglia.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Kang, 2018, Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau, J Exp Med source

      Not checked in the free run.

    • cites [88] Krasemann, 2017, The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases, Immunity. source

      Not checked in the free run.

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

    Study design and conductnone given

    All subjects gave written informed consent in accordance with the Declaration of Helsinki.

    “All subjects gave written informed consent in accordance with the Declaration of Helsinki.”
    Quote in the paperNot a substantial claim
55 of 55

  • The paper relies on this without support.

    The TASTPM mouse model demonstrates a more severe pathological burden than either the APP or PS1 mutation alone.

    “Amongst the mouse models of AD available from the Mouseac project, we chose to analyze the TASTPM model because it involves two mutant, disease-causing transgenes (APP and PS1) identified in human familial AD cases and demonstrates a more severe pathological burden than either mutation alone.”

  • The paper relies on this without support.

    The TASTPM mouse model involves two mutant, disease-causing transgenes (APP and PS1) identified in human familial AD cases.

    “Amongst the mouse models of AD available from the Mouseac project, we chose to analyze the TASTPM model because it involves two mutant, disease-causing transgenes (APP and PS1) identified in human familial AD cases and demonstrates a more severe pathological burden than either mutation alone.”

  • The paper relies on this without support.

    The P301L-tau transgenic mouse model models frontotemporal lobar degeneration (FTLD).

    “P301L-tau transgenic mice, which model a related neurodegenerative disorder, frontotemporal lobar degeneration (FTLD).”

  • The paper relies on this without support.

    AD shows a sex-specific incidence.

    “Given that AD shows a sex-specific incidence and findings indicating that microglia show sex-specific differentiation and gene expression profiles in adult mice (27–29), we also examined whether there was a statistical interaction between AD diagnosis and sex (i.e., Gene expression = Diagnosis × Sex + covariates), using the covariate selections described above.”

  • The paper relies on this without support.

    Publicly available brain tissue samples are limited and many native microglial markers are shared with other ostensibly similar cell populations.

    “These characteristics are especially important for native microglia in brain tissue—publicly available brain tissue samples are limited and many native microglial markers are shared with other ostensibly similar cell populations (e.g., infiltrating peripheral macrophages).”

  • The paper relies on this without support.

    Mouse models often mimic only limited aspects of the corresponding human neuropathology.

    “Further, mouse models often mimic only limited aspects of the corresponding human neuropathology.”

  • The paper relies on this without support.

    The major advantage of scRNAseq and mass cytometry is that they enable unbiased, global profiling of gene expression uninfluenced by changes in cellularity, as well as characterization of cell-type fluctuations as a function of anatomy, age, and disease.

    “The major advantage of these techniques is that they enable unbiased, global profiling of gene expression uninfluenced by changes in cellularity, as well as characterization of cell-type fluctuations as a function of anatomy, age, and disease.”
7 of 7

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?

  • TMEM119 is stably and specifically expressed in microglia and can be used to distinguish microglia from resident and infiltrating macrophages.

    “TMEM119 has been shown to be stably and specifically expressed in microglia [41,44], and it can be used to distinguish microglia from resident and infiltrating macrophages [41].”

    From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [44]

    The Introduction describes TMEM119 as a specific microglial marker that distinguishes microglia from other myeloid cells, including perivascular and infiltrating macrophages. The Methods also calls it a highly specific, well-validated marker. Neither passage establishes that its expression is stable, so that part of the claim is unsupported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • GPR34 encodes an inhibitory G-protein coupled receptor found on microglia that is overexpressed in regions of the brain affected by neurodegeneration in both humans and mice.

    “GPR34 (FC = 1.36, p = 0.002) encodes an inhibitory G-protein coupled receptor found on microglia which is overexpressed in regions of the brain affected by neurodegeneration in both humans and mice [10].”

    From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [10]

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.

  • Figure 3 points to the wrong table for the TASTPM analysis

    Minor

    Figure 3 cites Table 4 for the joint analysis of TASTPM heterozygotes and homozygotes, but Table 4 contains healthy-human regional enrichment results. The TASTPM mouse results are in Table 5.

1 of 1

The citation lists haven’t been fetched yet

References 114 · Cited by 83

Authors
Bonham, L. W., Sirkis, D. W., & Yokoyama, J. S.
Affiliations
University of California, San Francisco (US)
Corresponding author
Yokoyama, Jennifer S.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2019-06-04
Volume
10
Pages
1170-1170
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2019.01170
PMC
PMC6557985
OpenAlex
W2948895486
Semantic Scholar
0edd64265ed348d6d0b4b83994b5586de7170409
Cited by
83
References
114
Citations by year
2026: 5 · 2025: 7 · 2024: 19 · 2023: 11 · 2022: 10 · 2021: 17 · 2020: 12 · 2019: 2
FWCI
4.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • Larry L. Hillblom Foundation
  • National Institute on Aging
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
microglia, Alzheimer's disease, aging, neurodegenerative diseases, microglial gene expression, TMEM119, co-expression analysis, sex differences, hippocampus, cortex, tauopathy, postmortem brain
MeSH terms
Aging, Animals, Autoimmune Diseases, Brain, Disease Models, Animal, Disease Susceptibility, Gene Expression Regulation, Hippocampus, Humans, Organ Specificity, Microglia, Neurodegenerative Diseases, Gene Expression Profiling, Mice, Genome-Wide Association Study, Frontotemporal Dementia, Transcriptome

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

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

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