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Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer’s disease.
Open accessAbstract
Resolving glial contributions to Alzheimer's disease (AD) is necessary because changes in neuronal function, such as reduced synaptic density, altered electrophysiological properties, and degeneration, are not entirely cell autonomous. To improve understanding of transcriptomic heterogeneity in glia during AD, we used single-nuclei RNA sequencing (snRNA-seq) to characterize astrocytes and oligodendrocytes from apolipoprotein (APOE) Ɛ2/3 human AD and age- and genotype-matched non-symptomatic (NS) brains. We enriched astrocytes before sequencing and characterized pathology from the same location as the sequenced material. We characterized baseline heterogeneity in both astrocytes and oligodendrocytes and identified global and subtype-specific transcriptomic changes between AD and NS astrocytes and oligodendrocytes. We also took advantage of recent human and mouse spatial transcriptomics resources to localize heterogeneous astrocyte subtypes to specific regions in the healthy and inflamed brain. Finally, we integrated our data with published AD snRNA-seq datasets, highlighting the power of combining datasets to resolve previously unidentifiable astrocyte subpopulations.
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“Recently, transcriptomic studies have shown changes not only in microglia and astrocytes but also in oligodendrocytes, the myelinating cells of the central nervous system, in both human AD tissue [5,6]”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [6]
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“This subcluster was enriched for genes involved in extracellular matrix organization [102, 135, 136], metabolic support [135, 137], and inflammatory modulation [138–141].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [102]
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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 [14]
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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 [14]
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“A snRNA‐seq study in human AD also reported downregulation of synaptic cell adhesion–related gene expression and enrichment terms in an oligodendrocyte cluster. 65 , 66”
From Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses (2026) · cites this paper as [65]
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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 [14]
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The impact of physical exercise on neuroinflammation mechanism in Alzheimer’s disease
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Mechanisms of astrocyte aging in reactivity and disease
Gildea, H. K., & Liddelow, S. A. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00810-7 · Cited by 45
“…of astrocytes may be under-represented in bulk or whole-brain samples, as astrocytes are difficult to capture relative to neurons and other cells [22], and investigators may prioritize maintaining key sequencing depth over understanding spatial context and cellular resolution in aging studies.”
Self-citationChronic oligodendrocyte injury in central nervous system pathologies
Molina-González, I., Miron, V. E., & Antel, J. P. (2022) · Communications Biology · doi:10.1038/s42003-022-04248-1 · Cited by 46
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Regulatory T cells decrease C3-positive reactive astrocytes in Alzheimer-like pathology
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“Multiple subtypes of reactive astrocytes may thus occur concomitantly and play an instrumental role in the pathophysiology of AD, as supported by recent single-nuclei RNAseq studies [33].”
Brain incoming call from glia during neuroinflammation: Roles of extracellular vesicles
D’Egidio, F., Castelli, V., d’Angelo, M., Ammannito, F., Quintiliani, M., & Cimini, A. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106663 · Cited by 39
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Astrocytes: The Stars in Neurodegeneration?
Dittlau, K. S., & Freude, K. (2024) · Biomolecules · doi:10.3390/biom14030289 · Cited by 39
“These astrocytic sub-states are likely modulated by the homeostatic need of their residing region and the nature of the pathological condition and might be dynamic during different disease states, thereby moving across a “reactive astrocyte spectrum” [21,22].”
The toxic metal hypothesis for neurological disorders
Pamphlett, R., & Bishop, D. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1173779 · Cited by 44
“(4) Yes (46) In cigarette smoke (47, 48) Extra-CNS organs Yes (49) Yes (50) Yes (4) Yes (51) In extra-CNS organs (25, 34–36, 52–56) Metabolic changes Yes (57) Yes (3, 58) Yes (59) Yes (51, 59) In endocrine organs (34, 35, 53, 55) Hallucinations Yes (60) Yes (61) Yes (62) Yes (63) In geniculate nuclei (64) Cells Select…”
BackgroundLopes, J. R. D., Zhang, X., Mayrink, J., Tatematsu, B. K., Guo, L., LeServe, D. S., Abou‐El‐Hassan, H., Rong, F., Dalton, M. J., Oliveira, M. G., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2309221120 · Cited by 38
“Studies showing activated microglia and astrocytes surrounding A β plaques suggest significant involvement of inflammatory pathways in the disease (6, 7, 10, 11).”
Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1
Tejwani, L., Ravindra, N. G., Lee, C., Cheng, Y., Nguyen, B., Luttik, K. P., Ni, L., Zhang, S., Morrison, L. M., Gionco, J. T., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.10.039 · Cited by 37
Proteomic profiling of interferon‐responsive reactive astrocytes in rodent and human
Prakash, P., Erdjument‐Bromage, H., O’Dea, M. R., Munson, C., Labib, D., Fossati, V., Neubert, T. A., & Liddelow, S. A. (2023) · Glia · doi:10.1002/glia.24494 · Cited by 41
“…IRRA-specific transcripts are present in the 5xFAD mouse model of AD (Hasel et al., 2021), so we chose a cohort of AD patient and age-matched non-symptomatic (NS) controls (Sadick et al., 2022) and stained formalin-fixed paraffin embedded frontal cortex samples for some of the top IRRA proteins.”
BackgroundSelf-citationAPOE and immunity: Research highlights
Kloske, C. M., Barnum, C. J., Batista, A. F., Bradshaw, E. M., Brickman, A. M., Bu, G., Dennison, J. L., Gearon, M. D., Goate, A., Haass, C., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13020 · Cited by 38
“65,73,74 What remains a bottleneck for the understanding of cellular heterogeneity is twofold: a lack of sub-state-specific culture systems to study the functional changes that occur; and second, a lack of genetic diversity in functional testing to determine if apoE isoform may alter not only gene…”
Self-citationDissecting the brain with spatially resolved multi-omics
Fangma, Y., Liu, M., Liao, J., Chen, Z., & Zheng, Y. (2023) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2023.04.003 · Cited by 39
Repeated head trauma causes neuron loss and inflammation in young athletes
Butler, M. L. M. D., Pervaiz, N., Breen, K., Calderazzo, S. M., Ypsilantis, P., Wang, Y., Breda, J. C., Mazzilli, S. A., Nicks, R., Spurlock, E., et al. (2025) · Nature · doi:10.1038/s41586-025-09534-6 · Cited by 57
“Astrocytes have a key role in brain homeostasis in tasks such as neuronal and BBB maintenance and become reactive following RHI exposure and in neurodegenerative disease 14,24 .”
Mosaic loss of Chromosome Y in aged human microgliaPreprint
Vermeulen, M., Pearse, R. V., Young‐Pearse, T. L., & Mostafavi, S. (2022) · Genome Research · doi:10.1101/gr.276409.121 · Cited by 35
Oligodendrocyte pathology in Huntington’s disease: from mechanisms to therapeutics
Bardile, C. F., Radulescu, C. I., & Pouladi, M. A. (2023) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2023.07.010 · Cited by 36
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“In addition to the Morabito and Lau datasets, we included a third postmortem human PFC snRNA-seq dataset (Sadick et al.) with more than 100,000 nuclei from 10 AD and 6 control samples (Fig S6A-B; [34]).”
BackgroundMethodInfluentialCapacity of astrocytes to promote axon growth in the injured mammalian central nervous system
Hemati-Gourabi, M., Cao, T., Romprey, M. K., & Chen, M. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.955598 · Cited by 32
“scRNA-seq revealed regional astrocyte diversity, defined transcriptomically, in the healthy brain and spinal cord of mice and humans (Saunders et al., 2018; Hasel et al., 2021; Li et al., 2022; Sadick et al., 2022).”
BackgroundLish, A. M., Ashour, N., Pearse, R. V., Galle, P. C., Orme, G. A., Heuer, S. E., Benoit, C. R., Alexander, K. D., Grogan, E. F. L., Terzioğlu, G., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115777 · Cited by 29
“44 This underrepresentation may be due to the preferential loss of astrocytes during preparation, likely because of their distinct biochemical and biophysical properties.”
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C9orf72 hexanucleotide repeat expansions impair microglial response in ALS
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Curcumin as a potential therapeutic agent for treating neurodegenerative diseases
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Glymphatic system clearance and Alzheimer’s disease risk: a CSF proteome-wide study
Cullell, N., Caruana, G., Elias-Mas, A., Delgado-Sánchez, A., Artero, C., Buongiorno, M., Almería, M., Ray, N. J., Corrêa, S. A. L., & Krupiński, J. (2025) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01612-7 · Cited by 29
Heterogeneity of Astrocyte Reactivity
Clayton, B. L. L., & Liddelow, S. A. (2025) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-112723-031738 · Cited by 33
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Astrocytes regulate neuronal network activity by mediating synapse remodeling
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Gabrielli, M., Tozzi, F., Verderio, C., & Origlia, N. (2022) · Cells · doi:10.3390/cells12010063 · Cited by 34
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Astrocyte diversity and subtypes: aligning transcriptomics with multimodal perspectives
Hennes, M., Richter, M. L., Fischer-Sternjak, J., & Götz, M. (2025) · EMBO Reports · doi:10.1038/s44319-025-00529-y · Cited by 35
“Interestingly, these injury/disease-induced changes could be either protective or detrimental for disease progression (Schober et al, 2022; Sofroniew, 2020; Endo et al, 2022; Patani et al, 2023; Sadick et al, 2022).”
Xia, H., Feng, Y., Zhu, H., Yang, D., Wang, C., Wang, Z., Zhang, H., Pan, W., Zhao, Y., Initiative, A. D. N., et al. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03432-1 · Cited by 30
“Further longitudinal human trials and animal studies are warranted to validate our fi ndings and elucidate the underlying molecular mechanisms.”
Yan, Q., Qin, Q., Zhang, S., Chen, F., Ru, Y., Zhong, Y., & Wu, G. (2025) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2025.2568606 · Cited by 28
“At the same time, oligodendrocytes undergo subtype-specific transcriptional reprogramming, transforming into disease-associated sub-types, upregulating immune genes such as MHC-I and exacerbating neuroinflammation (Sadick et al. 2022).”
Albert‐Gascó, H., Smith, H., Alvarez‐Castelao, B., Swinden, D., Halliday, M., Janaki‐Raman, S., Butcher, A. J., & Mallucci, G. R. (2023) · Brain · doi:10.1093/brain/awad313 · Cited by 30
“The astrocytic nascent proteome showed more variability in disease versus control and trazodone-treated mice, reflecting the phenotypic variability and mixed profiles derived from varying activation states of astrocytes in disease, 55,56 but the groups still cluster as the others (Fig.”
BackgroundA Review of the Application of Spatial Transcriptomics in Neuroscience
Zhang, L., Xiong, Z., & Xiao, M. (2024) · Interdisciplinary Sciences: Computational Life Sciences · doi:10.1007/s12539-024-00603-4 · Cited by 29
Insulin and IGF-1 elicit robust transcriptional regulation to modulate autophagy in astrocytes
Geffken, S. J., Moon, S., Smith, C. O., Tang, S. S., Lee, H. H., Lewis, K., Wong, C. W., Huang, Y., Huang, Q., Zhao, Y.-T., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101647 · Cited by 26
“Dysregulation of astrocyte functions may play crucial roles in the development of many neurological conditions [31,32].”
BackgroundFunction and therapeutic value of astrocytes in diabetic cognitive impairment
Meng, F., Fu, J., Zhang, L., Guo, M., Zhuang, P., Yin, Q., & Zhang, Y. (2023) · Neurochemistry International · doi:10.1016/j.neuint.2023.105591 · Cited by 26
Are we there yet? Exploring astrocyte heterogeneity one cell at a time
O’Dea, M. R., & Hasel, P. (2024) · Glia · doi:10.1002/glia.24621 · Cited by 27
Self-citationZhang, Y., Li, T., Wang, G., & Ma, Y. (2024) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-024-01499-w · Cited by 27
“…examined samples were cortical, including temporal cortex, entorhinal cortex, middle frontal gyrus cortex, prefrontal cortex, and dlPFC (Pfisterer et al. 2020a; Maynard et al. 2021; Wu et al. 2023; Sadick et al. 2022; Nagy et al. 2020; Mathys et al. 2019; Grubman et al. 2019; Agarwal et al. 2020).”
Background
Metadata
- Authors
- Sadick, J. S., O’Dea, M. R., Hasel, P., Dykstra, T., Faustin, A., & Liddelow, S. A.
- Affiliations
- New York University (US)
- NYU Langone Health (US)
- Corresponding author
- Liddelow, Shane A.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2022-06
- Volume
- 110
- Issue
- 11
- Pages
- 1788-1805.e10
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC9167747
- OpenAlex
- W4225491855
- Cited by
- 415
- References
- 106
- Citations by year
- 2026: 89 · 2025: 93 · 2024: 103 · 2023: 90 · 2022: 38
- FWCI
- 53.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 365 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Icahn School of Medicine at Mount Sinai
- NIH (T32AG052909)
- Cure Alzheimer's Fund
- Rhode Island Hospital
- Blas Frangione Foundation
- University of Texas MD Anderson Cancer Center
- Presbyterian Historical Society (P30 AG08051)
- School of Medicine, New York University
- Stanford Genome Technology Center
- Alzheimer's Association
- Alzheimer’s Research UK
- Alzheimer's Disease Research Center, University of Pittsburgh
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, astrocytes, oligodendrocytes, glial heterogeneity, astrocyte subtypes, single-nucleus RNA sequencing, transcriptomic changes, neuroinflammation, spatial transcriptomics, data integration
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Humans, Neuroglia, Oligodendroglia, RNA, Small Nuclear, Mice, Transcriptome
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