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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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BackgroundInfluential
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Diverse signaling mechanisms and heterogeneity of astrocyte reactivity in Alzheimer's disease
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HDAC Inhibitors recapitulate Human Disease-Associated Microglia Signatures in vitroPreprint
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BackgroundAdvances in the Study of APOE and Innate Immunity in Alzheimer’s Disease
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InfluentialMicroglia protein profiles in CSF across Alzheimer’s disease clinical stages
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“The diversity of glial transcription in Alzheimer’s and the response of both astrocytes and microglia to pathological protein clearance and inflammation are associated [15].”
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“After that, Smith et al. (70) found that the inflammatory pathway was significantly enriched in astrocytes in the sequencing of the dead brain, and the phagocytosis, inflammation and protein inhibition pathways were enriched in microglia and perivascular macrophages, with a high content of tissue amyloid protein.”
BackgroundCSF proteomics of semorinemab Alzheimer’s disease trials identifies cell-type specific signatures
Abdel‐Haleem, A. M., Casavant, E., Tóth, B. I., Teng, E., Monteiro, C., Pandya, N. J., Glock, C., Hoogenraad, C. C., Friedman, B. A., Yeh, F. L., et al. (2025) · Brain · doi:10.1093/brain/awaf200 · Cited by 8
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Identifying Tipping Points during Healthy Brain Aging through Single‐Nucleus Transcriptomic Analysis
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Analyzing the glial proteome in Alzheimer’s disease
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BackgroundMicroglia Heterogeneity: A Single-cell Concerto
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“Moreover, a recent study found that significant differences in AD risk genes expressed in microglia (APOE, MS4A6A, PILRA) were related to tissue amyloid or pTau expression (Smith et al., 2022).”
BackgroundMüller Glial Kir4.1 Channel Dysfunction in APOE4 ‐ KI Model of Alzheimer's Disease
Abhyankar, S. D., Xiao, Y., Mahajan, N. S., Luo, Q., Cummins, T., Oblak, A. L., Lamb, B. T., Corson, T. W., & Bhatwadekar, A. D. (2026) · Glia · doi:10.1002/glia.70119 · Cited by 3
“1 expression was found in the human AD cortex (Smith et al. 2022) and in the human AD middle temporal gyrus (Liu et al. 2024).”
InfluentialInferring gene regulatory networks by hypergraph variational autoencoderPreprint
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“Spatial transcriptomics, snRNA-seq, EV profiling, complement-related signatures, ligand–receptor interaction maps, and metabolic readouts of Trp/AHR signaling could together define a more informative disease atlas (Smith et al., 2022; Liu et al., 2024).”
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“57 60 Similarly, there is evidence suggesting that body composition factors, such as obesity, can in fl uence disease activity, extra-intestinal manifestations, and response to treatment.”
BackgroundReduced Expression of CLEC4G in Neurons Is Associated with Alzheimer’s Disease
Feng, X., Qi, F., Huang, Y., Zhang, G., & Deng, W. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094621 · Cited by 2
“…decrease in the expression levels of the CLEC4G gene during this process, while genes such as BACE1, PSEN1, and NPC1 showed a pronounced upward This outcome suggests that CLEC4G expression decreases as AD progresses, corroborating the results of the bulk RNA-seq analysis shown in Figure 5. trend.”
MethodResultInfluentialFANS Unfixed: Isolation and Proteomic Analysis of Mouse Cell Type-Specific Brain Nuclei
Bedwell, L., Mavrotas, M., Demchenko, N., Yaa, R. M., Willis, B., Demianová, Z., Syed, N., Whitwell, H. J., & Nott, A. (2024) · Journal of Proteome Research · doi:10.1021/acs.jproteome.4c00161 · Cited by 3
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Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric AßPreprint
Matafora, V., Gorb, A., Noble, W., Bachi, A., Perez-Nievas, B., & Jimenez-Sanchez, M. (2023) · bioRxiv · doi:10.1101/2023.01.18.523916
“Single cell RNAseq and immunohistochemical studies have frequently reported that genes involved in proteostasis and chaperone-mediated responses are up-regulated specifically in astrocytes in AD (Grubman et al. 2019; Lau et al. 2020; Smith et al. 2021; Viejo et al. 2022) which, together with our study, may imply that…”
BackgroundAmossé, Q., Tournier, B. B., Badina, A. M., Marchand-Maillet, L., Abjean, L., Lengacher, S., Fancy, N. N., Smith, A. M., Leung, Y.-Y., Santer, V., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.29.564621 · Cited by 2
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Proteome-wide association study identifies novel Alzheimer's disease-associated proteins
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“51,52 Several studies showed that PILRA is an AD risk gene 53,54 and a recently recognized AD-associated inhibitory receptor.”
Decoding Alzheimer's Disease One Cell Class at a Time
Darvas, M., Cook, D. G., & Scimemi, A. (2026) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-026-01685-y · Cited by 1
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“32,33 The BBB also functions as a dynamic regulatory interface for protein ef fl ux and neuroimmune communication.”
Hwang, Y.-Y., Oh, C.-I., Lee, J.-P., Lee, S.-M., Park, D., Oh, I.-H., Kim, T., Jeong, O. C., Ahn, J., Kim, Y., et al. (2026) · Molecular & Cellular Toxicology · doi:10.1007/s13273-026-00624-8 · Cited by 1
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“Because fi xed A1/A2 categories oversimplify astrocyte biology, reactive astrocytes should be described as heterogeneous states shaped by disease stage, brain region, plaque proximity, vascular context, and local glial signaling (35, 36).”
Kumar, S., Singh, J., Maurya, V. K., Ansari, S., Srivastava, C., Malhotra, H., Babu, S., & Saxena, S. K. (2026) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlag025 · Cited by 1
Molecular signaling pathways shaping astrocyte–microglia crosstalk in health and disease
Argente-Arizón, P., & Monge-Ochoa, B. (2026) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2026.1828420 · Cited by 1
“Likewise, single-cell and bulk transcriptomic studies in human brain tissue have revealed marked species-specific differences in astrocytic and microglial responses to pathological protein clearance and inflammation, including divergent expression of Alzheimer’s disease risk genes such as CLU, MEF2C, APOE, and PILRA (Smi…”
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Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-betaPreprint
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“3 43 Introduction 44 Astrocytes are essential for maintaining homeostasis, synaptic plasticity and the 45 inflammatory response in the central nervous system [1] and show disease-associated profiles 46 in AD [2-5].”
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Cellular biology of the central nervous system
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TSPO contributes to neuropathology and cognitive deficits in Alzheimer’s diseasePreprint
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Additional file 1 of Alzheimer’s disease-related transcriptional sex differences in myeloid cells
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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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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