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Diverse human astrocyte and microglial transcriptional responses to Alzheimer’s pathology
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Abstract
To better define roles that astrocytes and microglia play in Alzheimer’s disease (AD), we used single-nuclei RNA-sequencing to comprehensively characterise transcriptomes in astrocyte and microglia nuclei selectively enriched during isolation post-mortem from neuropathologically defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Significant differences in glial gene expression (including AD risk genes expressed in both the astrocytes [ CLU , MEF2C , IQCK ] and microglia [ APOE , MS4A6A , PILRA ]) were correlated with tissue amyloid or pTau expression. The differentially expressed genes were distinct between with the two cell types and pathologies, although common (but cell-type specific) gene sets were enriched with both pathologies in each cell type. Astrocytes showed enrichment for proteostatic, inflammatory and metal ion homeostasis pathways. Pathways for phagocytosis, inflammation and proteostasis were enriched in microglia and perivascular macrophages with greater tissue amyloid, but IL1-related pathway enrichment was found specifically in association with pTau. We also found distinguishable sub-clusters in the astrocytes and microglia characterised by transcriptional signatures related to either homeostatic functions or disease pathology. Gene co-expression analyses revealed potential functional associations of soluble biomarkers of AD in astrocytes ( CLU ) and microglia ( GPNMB ). Our work highlights responses of both astrocytes and microglia for pathological protein clearance and inflammation, as well as glial transcriptional diversity in AD.
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“resulting in over 100,000 astrocyte nuclei in each brain region with ≈6,000 average total number of reads and ≈2,500 average total number of genes detected, which is orders of magnitude higher than previous studies9–15”
From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [15]
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“may have confounded previous studies that compared only control and severe AD donors or grouped late- and end-stage donors (Braak stage V/VI) together9–15”
From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [15]
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“We found increased numbers of senescence genes upregulated in both microglia (YPEL3, IQGAP2, SQSTM1) and astrocytes (GLB1, SQSTM1, MRAS) with greater levels of tissue β-amyloid densities [66] (Supplementary Fig. 7a, b, Supplementary data S7).”
From Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics (2024) · cites this paper as [66]
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“Finally, we also explored senescence pathway expression in the six astroglial sub-populations that we described previously [66], but did not find that any of these sub-populations showed greater expression of the senescence gene set with AD (Fig. 6c, d, Supplementary Fig. 10c).”
From Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics (2024) · cites this paper as [66]
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“our sample sizes are similar to those reported in previous publications9–17”
From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [15]
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“The study found that microglial transcripts were most highly positively associated with tissue Aβ and tissue pTau density.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [145]
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BackgroundLate onset Alzheimer’s disease genetics implicates microglial pathways in disease risk
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“Activated astrocytes and microglia are found around amyloid plaques [52] and genes associated with AD risk are enriched in both cell types, particularly in microglia [12, 56].”
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Single-nucleus RNA-seq identifies Huntington disease astrocyte states
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APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer’s disease
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“Our analytical approach for addressing heterogeneity in the samples also differs from most prior studies (although it is not without similar precedents [7, 41]).”
BackgroundResultSerrano-Pozo, A., Muzikansky, A., Gómez-Isla, T., Growdon, J. H., Betensky, R. A., Frosch, M. P., & Hyman, B. T. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182933788 · Cited by 226 · cited 1×
“Activated astrocytes and microglia are found around amyloid plaques [52] and genes associated with AD risk are enriched in both cell types, particularly in microglia [12, 56].”
BackgroundKim, W.-K., Alvarez, X., Fisher, J., Bronfin, B., Westmoreland, S., McLaurin, J., & Williams, K. (2006) · The American Journal of Pathology · doi:10.2353/ajpath.2006.050215 · Cited by 225 · cited 2×
“Clustering parameters selected to distinguish PVM [identified by markers such as CD163, MRC1 (CD206), and MSR1 [29]] also identified three clusters of nuclei (designated Micro1, 2, and 3) expressing different sets of microglial marker genes (Fig.”
BackgroundTGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and FunctionPreprint
Meyers, E. A., & Kessler, J. A. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a022244 · Cited by 213
The role of Wnt signaling in neuronal dysfunction in Alzheimer's Disease
Inestrosa, N. C., & Toledo, E. M. (2008) · Molecular Neurodegeneration · doi:10.1186/1750-1326-3-9 · Cited by 207
Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis
Ward, M. E., Chen, R., Huang, H.-Y., Ludwig, C., Telpoukhovskaia, M., Taubes, A., Boudin, H., Minami, S. S., Reichert, M., Albrecht, P., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aah5642 · Cited by 193 · cited 1×
“7c,d, online resource), as well as those for genes associated with risks for other neurodegenerative disorders (LRRK2, SNCA and GPNMB, associated with Parkinson’s disease [8], and GRN, associated with ceroid lipofuscinosis [71] and frontotemporal dementia [4]).”
BackgroundVilalta, A., & Brown, G. C. (2017) · FEBS Journal · doi:10.1111/febs.14323 · Cited by 180 · cited 1×
“By contrast, “core” or homeostatic astrocyte transcripts, such as those for glutamate transporters SLC1A3 and SLC1A2 or for IL-33 (CSF1R ligand, which promotes microglial synaptic remodelling [69]), were downregulated.”
BackgroundHüttenrauch, M., Ogorek, I., Klafki, H., Otto, M., Stadelmann, C., Weggen, S., Wiltfang, J., & Wirths, O. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0612-3 · Cited by 166 · cited 2×
“These analyses also highlighted potential functional relationships of GPNMB (concentrations of the protein product of which are increased in brain samples and cerebrospinal fluid of sporadic AD patients [23]) with a diverse group of genes connected to transcription factors whose regulons were up-regulated with amyloid…”
BackgroundImmature excitatory neurons develop during adolescence in the human amygdala
Sorrells, S. F., Paredes, M. F., Velmeshev, D., Herranz‐Pérez, V., Sandoval, K., Mayer, S., Chang, E. F., Insausti, R., Kriegstein, A. R., Rubenstein, J. L. R., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10765-1 · Cited by 147 · cited 1×
“MAST was used to identify genes differentially expressed (associated) with histopathological features (using pTau or amyloid-beta as markers) [14, 59] to perform zero-inflated regression analysis by fitting a mixed model.”
MethodTranscriptional profiling of microglia; current state of the art and future perspectives
Gerrits, E., Heng, Y., Boddeke, E. W. G. M., & Eggen, B. J. L. (2020) · Glia · doi:10.1002/glia.23767 · Cited by 140
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CD74 interacts with APP and suppresses the production of Aβ
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Imbalance between pro-oxidant and pro-antioxidant functions of zinc in disease
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“The latter proteins modulate neuroprotective superoxide dismutases through their regulation of Cu and Zn concentrations in extra- and intracellular compartments [20, 21, 54].”
BackgroundThe Chaperone Activity of Clusterin is Dependent on Glycosylation and Redox Environment
Rohne, P., Prochnow, H., Wolf, S., Renner, B., & Koch-Brandt, C. (2014) · Cellular Physiology and Biochemistry · doi:10.1159/000366365 · Cited by 70
Significance of metallothioneins in aging brain
SHARMA, S. K., & Ebadi, M. (2014) · Neurochemistry International · doi:10.1016/j.neuint.2013.12.009 · Cited by 70 · cited 1×
“The latter proteins modulate neuroprotective superoxide dismutases through their regulation of Cu and Zn concentrations in extra- and intracellular compartments [20, 21, 54].”
BackgroundTranscriptional signatures of tau and amyloid neuropathology
Castanho, I., Murray, T. K., Hannon, E., Jeffries, A., Walker, E., Laing, E., Baulf, H., Harvey, J., Bradshaw, L., Randall, A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.01.063 · Cited by 62 · cited 1×
“Our analytical approach for addressing heterogeneity in the samples also differs from most prior studies (although it is not without similar precedents [7, 41]).”
ResultSun, Y., Senger, K., Baginski, T. K., Mazloom, A., Chinn, Y., Pantua, H., Hamidzadeh, K., Ramani, S. R., Luis, E., Tom, I., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.286633 · Cited by 44 · cited 1×
“Both amyloid-beta and pTau pathology were associated with increased expression of genes implicated in integrin interactions with laminin and fibrillin, the APP (astrocyte)–CD74 (microglia) ligand pair, which can suppress amyloid-beta production [37], and inferred CD99 (astrocyte)–PILRA (microglia) interactions that ma…”
BackgroundBMP4 overexpression induces the upregulation of APP/Tau and memory deficits in Alzheimer’s disease
Zhang, X., Li, J., Ma, L., Xu, H., Cao, Y., Liang, W., Ma, J., Wang, Z. P., & Li, Y. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00435-x · Cited by 29
Roles and Therapeutic Potential of Metallothioneins in Neurodegenerative Diseases
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“The latter proteins modulate neuroprotective superoxide dismutases through their regulation of Cu and Zn concentrations in extra- and intracellular compartments [20, 21, 54].”
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“Independent of this, amyloid-beta pathology alone was associated with higher probabilities of CXCL12 (microglial)–CXCR7 (astrocytic) interactions implicated in neurogenesis and learning [38, 66], BMP4 (microglial)–BMP1RA Fig.”
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scFlow: A Scalable and Reproducible Analysis Pipeline for Single-Cell RNA Sequencing DataPreprint
Khozoie, C., Fancy, N. N., Marjaneh, M. M., Murphy, A. E., Matthews, P. M., & Skene, N. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.16.456499 · Cited by 20
Self-citationSingle nucleus sequencing fails to detect microglial activation in human tissuePreprint
Thrupp, N., Frigerio, C. S., Wolfs, L., Skene, N., Poovathingal, S., Fourne, Y., Matthews, P. M., Theys, T., Mancuso, R., Strooper, B. D., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.13.035386 · Cited by 11 · cited 1×
“Even so, the nuclear transcriptome may be biased relative to that from a whole cell, potentially reducing the power to detect some genes reported from studies of related pathologies in mouse models [64].”
BackgroundSelf-citation[Nucleic acid metabolism of hair cells and spiral ganglion cells].
Kon, I., & Ito, I. (1972) · PubMed · Cited by 6
Flagged first, then by citations
Cited by
Sorted by citations
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
Gao, C., Jiang, J., Tan, Y., & Chen, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01588-0 · Cited by 1,616
“145 These results suggest that microglia respond to the pathology of AD.”
Neuroinflammation in Alzheimer disease
Heneka, M. T., van der Flier, W. M., Jessen, F., Hoozemanns, J., Thal, D. R., Boche, D., Brosseron, F., Teunissen, C., Zetterberg, H., Jacobs, A. H., et al. (2025) · Nature Reviews Immunology · doi:10.1038/s41577-024-01104-7 · Cited by 638
“Nevertheless, isolation of microglial cells from AD brains and subsequent analysis of the transcriptome has provided important insights into microglial cell activation states 220,222 .”
Nutma, E., Fancy, N. N., Weinert, M., Tsartsalis, S., Marzin, M. C., Muirhead, R. C. J., Falk, I. N., Breur, M., de Bruin, J., Hollaus, D., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40937-z · Cited by 204
“Quality control, sampleintegration, dimension reduction and clustering were performed using default parameters as previously described 41,83 .”
InfluentialSelf-citationDolan, M.-J., Therrien, M., Jereb, S., Kamath, T., Gazestani, V., Atkeson, T., Marsh, S. E., Goeva, A., Lojek, N. M., Murphy, S., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01558-2 · Cited by 185
Human Microglia Show Unique Transcriptional Changes in Alzheimer's Disease
Prater, K. E., Green, K. J., Mamde, S., Sun, W., Cochoit, A., Smith, C. L., Chiou, K. L., Heath, L., Rose, S. E., Wiley, J., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00424-y · Cited by 164
Metadata
- Authors
- Smith, A. M., Davey, K., Tsartsalis, S., Khozoie, C., Fancy, N., Tang, S. S., Liaptsi, E., Weinert, M., McGarry, A., Muirhead, R. C. J., Gentleman, S., Owen, D. R., & Matthews, P. M.
- Affiliations
- Hammersmith Hospital (GB)
- University of Geneva (CH)
- Corresponding author
- Matthews, Paul M.
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2021-11-12
- Volume
- 143
- Issue
- 1
- Pages
- 75-91
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC8732962
- OpenAlex
- W3214651914
- Cited by
- 209
- References
- 81
- Citations by year
- 2026: 43 · 2025: 41 · 2024: 50 · 2023: 49 · 2022: 24 · 2021: 1
- FWCI
- 21.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Science Foundation
- Alzheimer's Society
- National Institute for Health and Care Research (NIHR202376, NF-SI-0514-10022)
- Parkinson's UK
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (191446)
- UK Dementia Research Institute
- Medical Research Council (MR/K501013/1, MR/N008219/1, MR/M024903/1, MR/T031891/1, MR/N026934/1, MC_PC_17114)
- NIHR Imperial Biomedical Research Centre
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, astrocytes, microglia, amyloid-beta, phosphorylated tau, single-nucleus RNA sequencing, postmortem brain, apolipoprotein E, clusterin, MEF2C, MS4A6A, proteostasis, inflammation, phagocytosis, metal homeostasis, perivascular macrophages, GPNMB, gene co-expression, disease biomarkers
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Astrocytes, Brain, Female, Humans, Male, Microglia, Transcriptome
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