Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution
Open accessAbstract
Microglia, the tissue-resident macrophages in the brain, are damage sensors that react to nearly any perturbation, including neurodegenerative diseases such as Alzheimer's disease (AD). Here, using single-cell RNA sequencing, we determined the transcriptome of more than 1,600 individual microglia cells isolated from the hippocampus of a mouse model of severe neurodegeneration with AD-like phenotypes and of control mice at multiple time points during progression of neurodegeneration. In this neurodegeneration model, we discovered two molecularly distinct reactive microglia phenotypes that are typified by modules of co-regulated type I and type II interferon response genes, respectively. Furthermore, our work identified previously unobserved heterogeneity in the response of microglia to neurodegeneration, discovered disease stage-specific microglia cell states, revealed the trajectory of cellular reprogramming of microglia in response to neurodegeneration, and uncovered the underlying transcriptional programs.
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Microglial activation can help clear pathogenic molecules from the brain but can also lead to chronic or excessive inflammation that exacerbates neurodegeneration.
“While microglial activation can help clear pathogenic molecules from the brain, it can also lead to chronic or excessive inflammation that exacerbates neurodegeneration (Mathys et al., 2017).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Mathys et al., 2017
The Introduction says microglia clear apoptotic cells, but it does not say they clear pathogenic molecules. The Discussion reports increased pro-inflammatory cytokines in responding microglia and suggests they may contribute to a cascade leading to neuronal death; it does not establish that chronic or excessive inflammation exacerbates neurodegeneration. (LLM, conf=0.85)
Experimental — accuracy not yet measuredApparent PLCG2 transcript upregulation in bulk cortical tissue is mostly related to microgliosis occurring as a consequence of neurodegeneration.
“However, normalization to microglia-specific genes (e.g., Abi3) and data from single-cell profiling of brain immune cells [6, 36, 37], suggest that apparent PLCG2 transcript upregulation in bulk tissue is mostly related to microgliosis occurring as a consequence of neurodegeneration.”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [37]
The Results section on microglial proliferation reports increased microglial density in the hippocampus of neurodegenerating CK-p25 mice. The Discussion also says that increased immune-related transcripts in tissue could reflect either changes in microglial expression or expansion of the microglial population, and finds evidence for both. Our copy does not establish that bulk-tissue PLCG2 upregulation is mostly due to microgliosis; searches for PLCG2 and Abi3 found no passage addressing that specific inference. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThese aggregated forms play leading roles in driving main pathogenic events in these neurodegenerative diseases with the active involvement of highly activated microglia, more recently referred to as disease-associated microglia.
“In fact, these aggregated forms play leading roles in driving main pathogenic events in these neurodegenerative diseases with the active involvement of highly activated microglia, more recently referred to as disease-associated microglia (Krasemann et al., 2017) (Keren-Shaul et al., 2017) (Mathys et al., 2017).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Mathys et al., 2017
The Introduction describes microglia responding to Aβ plaques, and the Discussion (‘Two Distinct Reactive Microglia Phenotypes in Neurodegeneration’; page unavailable) reports that the authors’ late-response microglia resemble disease-associated microglia. The paper does not establish that aggregated forms drive the main pathogenic events in these diseases, and it says whether the DAM-like response is protective, neutral, or harmful remains unknown. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn longer-term neurodegenerative models, such as AD, distinct temporal microglial activation states emerge.
“In longer-term neurodegenerative models, such as AD, distinct temporal microglial activation states emerge61.”
From A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions (2026) · cites this paper as [61]
An effect of TET2 in cell cycle regulation cannot be discarded in response to proinflammatory challenge, in line with RNA-seq data.
“A typical early feature of activated microglia is cell proliferation (Mathys et al., 2017), hence an effect of TET2 in cell cycle regulation cannot be discarded in response to proinflammatory challenge in line with our RNA-seq data.”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Mathys et al., 2017
In a severe neurodegeneration model (CK-p25 mouse model) for AD, 'late-stage' activated microglia is characterized by the expression of many Type I and Type II Interferon response genes.
“In fact, using single-cell RNA sequencing of microglia at different stages in a severe neurodegeneration model (CK-p25 mouse model) for AD (Mathys et al., 2017), the authors described that 'late-stage' activated microglia is characterized by the expression of many Type I and Type II Interferon response genes.”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Mathys et al., 2017
Microglia expressing interferon response genes in the CK-p25 model look quite different from the IRMs described here.
“Microglia expressing interferon response genes have been described as a late response to neurodegeneration in a CK-p25 model (Mathys et al., 2017); however, these look quite different from the IRMs described here.”
From The Major Risk Factors for Alzheimer’s Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques (2019) · cites this paper as Mathys et al., 2017
The activated microglia cluster had increased expression of genes upregulated in microglia during late response to neurodegenerative disease.
“microglia during late response to neurodegenerative disease [31]”
From Culture shock: microglial heterogeneity, activation, and disrupted single-cell microglial networks in vitro (2022) · cites this paper as [31]
Cfb has been previously linked to neurodegeneration.
“Interestingly, Cfb has been previously linked to neurodegeneration 38 .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [38]
Increased levels of Trem2 have been detected in disease-associated microglia compared to microglia in a homeostatic state.
“Moreover, increased levels of Trem2 have been detected in disease-associated microglia compared to microglia in a homeostatic state (37).”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [37]
The Discussion section, “Two Distinct Reactive Microglia Phenotypes in Neurodegeneration” (page unavailable), describes a Trem2-dependent transition to a disease-associated microglia stage and lists genes upregulated in those cells, but does not list Trem2 among them. A search for Trem2 found no passage comparing its levels in disease-associated and homeostatic microglia. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn different single cell RNAseq of microglia in different AD models, the expression of TET2 was found not to be upregulated.
“It is noteworthy to mention that in different single cell RNAseq of microglia in different AD models, the expression of TET2 was found not to be upregulated (Krasemann et al., 2017) (Keren-Shaul et al., 2017) (Mathys et al., 2017).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Mathys et al., 2017
The Results passages describe single-cell microglial gene-expression changes in the CK-p25 model, but do not report whether TET2 was upregulated. Searches for “TET2” and “Tet2 expression upregulated microglia” found no passage addressing TET2, so our copy cannot verify the claim attributed to Mathys et al. (LLM, conf=0.72)
Experimental — accuracy not yet measuredDisease-associated microglia have a transcriptional signature distinct from homeostatic microglia, which declines in mouse Alzheimer's disease models.
“Such activated microglia, which have been referred to as disease-associated microglia (DAM), has a transcriptional signature quite distinct from that of homeostatic microglia that markedly declines in mouse models of AD10,11,12.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [12]
The microglial gene changes were highly concordant between the 7-month and 15-month datasets and with previously published single-cell RNA-seq of sorted microglia.
“These results were highly concordant between the 7-month- and 15-month-old datasets (Fig. 2d) and with previously published single cell RNA-seq data of sorted microglia10,11,12.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [12]
Detection of localized populations of microglia expressing interferon-response genes may assist in identifying foci of neuronal injury or degeneration.
“Therefore, the detection of localized populations of microglia expressing interferon-response genes may assist in identifying foci of neuronal injury or degeneration (Mathys et al., 2017).”
From Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain (2018) · cites this paper as Mathys et al., 2017
scRNA-seq studies identified disease-associated microglia (DAMs) in mouse models and human patient specimens of AD.
“scRNA-seq studies identified a specific microglial response state, called disease-associated microglia (DAMs), in mouse models and human patient specimens of AD.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [16]
A growing number of non-viral diseases are characterized by the presence of a similar IFN transcriptional signature, evident within the microglial transcriptome itself as upregulated interferon signalling gene sets in cells isolated from both an Alzheimer's disease-like model of neurodegeneration as well as ageing humans.
“A growing number of non-viral diseases are characterized by the presence of a similar IFN transcriptional signature (Mostafavi et al. , 2016) evident within the microglial transcriptome itself as upregulated interferon signalling gene sets in cells isolated from both an Alzheimer's disease-like model of neurodegeneration as well as ageing humans (Galatro et al. , 2017; Mathys et al. , 2017).”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Mathys et al., 2017
In a mouse Alzheimer disease model, microglia with co-regulated type 1 and type 2 interferon-responsive gene modules and proliferation appear early after neuronal injury.
“In a mouse AD model, microglia typified by the expression of modules of co-regulated type 1 and type 2 IFN-responsive genes and their proliferation were shown to be present as an early response to neuronal injury142.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [142]
These genes form part of a common neurodegenerative and disease-associated signature that multiple groups have observed.
“which are now known to be part of a common neurodegenerative52 and disease-associated signature that has been observed by several groups26,111,141,142”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [142]
Two distinct reactive microglial phenotypes were identified at later stages of neurodegeneration.
“Moreover, two distinct reactive microglial phenotypes were identified at later stages of neurodegeneration142.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [142]
Homeostatic microglia gradually adopt a unique phagocytic disease-associated microglia (DAM) phenotype in neurodegenerative disease, chronic neuroinflammatory states, and advanced aging.
“Recent transcriptomics studies have shown that homeostatic microglia gradually adopt a unique phagocytic disease-associated microglia (DAM) phenotype in neurodegenerative disease, chronic neuroinflammatory states as well as advanced aging [9–12].”
From Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease (2018) · cites this paper as [11]
The cerebellar microglia phenotype resembles microglia during early brain development and microglia associated with neurodegenerative disease.
“The cerebellar microglia phenotype is reminiscent of microglia during early brain development9,10 as well as microglia associated with neurodegenerative disease11–13.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [11]
Cerebellar microglia show increased expression of genes characteristic of immature microglia and genes expressed in neurodegenerative disease-associated microglia.
“Furthermore, cbMg show an increase in the expression of genes characteristic of immature microglia9,10, as well as genes that are expressed in neurodegenerative disease-associated microglia (such as primed microglia, MGnD, and DAMs)11–13 (Supplementary Fig. 5c,d, Supplementary Table 4).”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [11]
Adult mouse cerebellar microglia show a primed/phagocytic phenotype characterized by less ramified morphology, reduced branching sites, decreased cell volume, and increased CD68+ lysosome content.
“cbMg in the adult mouse brain show a primed/phagocytic microglia phenotype11–13 characterized by a less ramified morphology, reduced branching sites (Supplementary Fig. 1a), decreased cell volume (Supplementary Fig. 1b,c), and an increase in CD68+ lysosome content (Fig. 1a, Supplementary Fig. 1b,c).”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [11]
A significant fraction of cerebellar microglia-expressed genes have been implicated in detection, engulfment, and catabolism of debris in peripheral macrophages carrying out cell clearance and in microglia associated with ageing and neurodegeneration.
“In particular, a significant fraction of the cbMg-expressed genes have been implicated in the detection, engulfment, and catabolism of debris both in peripheral macrophages carrying out cell clearance21 as well as in microglia associated with ageing and neurodegeneration11–13.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [11]
The increase in clearance-associated genes and reduction in surveillance-related genes in PRC2-deficient striatal microglia are reminiscent of transcriptional changes observed in microglia during neurodegenerative disease.
“The increase in clearance-associated genes and the reduction in surveillance-related genes in PRC2-deficient stMg are reminiscent of transcriptional changes observed in microglia during neurodegenerative disease11–13 (Supplementary Fig. 11h).”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [11]
This reduction in homeostatic microglia genes is another key characteristic feature of early microglia progenitors and microglia exposed to dying neurons during different diseases.
“This is another key characteristic feature of early microglia progenitors9,10 as well as microglia exposed to dying neurons during different diseases11–13.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [11]
In PRC2-deficient stMg and cxMg, complement and pro-inflammatory genes typically linked to microglial activation in neurodegeneration are not increased.
“While PRC2-deficient stMg and cxMg show no up-regulation of complement or pro-inflammatory genes generally associated with microglia activation during neurodegeneration11–13,34, it is still plausible that their aberrant clearance activity may lead to the enhanced engulfment of C1q/C3-tagged spines, the presence of which increases with age44.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [11]
The cerebellar microglia-specific clearance gene expression pattern significantly overlaps with the signature of microglia associated with neurodegeneration and early brain development.
“We found that the cbMg-specific clearance gene expression pattern significantly overlaps with the signature of microglia associated with neurodegeneration11–13 and early brain development9,10, two stages of life characterized by enhanced neuronal attrition and heightened microglia clearance activity.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [11]
Increased proliferation has been associated with 'activated' pro-inflammatory microglia in animal models.
“In contrast, increased proliferation has been associated with ‘activated’ pro-inflammatory microglia in animal models [84,153–155].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [155]
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A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation
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“…to AD by analyzing published single-cell gene expression datasets of immune cells from AD patients (Grubman et al., 2019; Lau et al., 2020; Mathys et al., 2019; Morabito et al., 2021; Xu and Jia, 2021; Zhou et al., 2020b) and mouse models (Keren-Shaul et al., 2017; Mathys et al., 2017; Fig.”
InfluentialSelf-citationGalectin-3 in Microglia-Mediated Neuroinflammation: Implications for Central Nervous System Diseases
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- Authors
- Mathys, H., Adaikkan, C., Gao, F., Young, J. Z., Manet, E., Hemberg, M., De Jager, P. L., Ransohoff, R. M., Regev, A., & Tsai, L.-H.
- Affiliations
- Massachusetts Institute of Technology (US)
- Wellcome Sanger Institute (GB)
- Biogen (United States) (US)
- Broad Institute (US)
- Corresponding author
- Tsai, Li-Huei
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 21
- Issue
- 2
- Pages
- 366-380
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5642107
- OpenAlex
- W2761726094
- Cited by
- 740
- References
- 38
- Citations by year
- 2026: 40 · 2025: 68 · 2024: 100 · 2023: 93 · 2022: 107 · 2021: 106 · 2020: 101 · 2019: 76 · 2018: 47 · 2012: 1
- FWCI
- 30.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Elsevier eBooks
- Funders
- JBP Foundation
- NIH (RF1 AG054321)
- Swiss National Science Foundation (P2BSP3_151885)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- microglial activation, neurodegeneration, Alzheimer's disease, hippocampus, microglial transcriptome, microglial heterogeneity, type I interferon response, microglial reprogramming
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cells, Cultured, Interferon Type I, Interferon-gamma, Macrophage Activation, Macrophages, Phenotype, Microglia, Gene Expression Profiling, Mice, Single-Cell Analysis, Transcriptome
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