The DOI matches its Crossref record; 107 of the 107 references it cites were found in a registry or an index.
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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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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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Citations
Cites
1 retracted
ADAMTS13 maintains cerebrovascular integrity to ameliorate Alzheimer-like pathology
Cao, Y., Xu, H., Zhu, Y., Shi, M.-J., Wei, L., Zhang, J., Cheng, S., Shi, Y., Tong, H., Kang, L., et al. (2019) · PLOS Biology · doi:10.1371/journal.pbio.3000313 · Cited by 31
RetractedFiji: an open-source platform for biological-image analysis
Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., et al. (2012) · Nature Methods · doi:10.1038/nmeth.2019 · Cited by 66,890
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Integrated analysis of multimodal single-cell data
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Comprehensive Integration of Single-Cell Data
Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W. M., Hao, Y., Stoeckius, M., Smibert, P., & Satija, R. (2019) · Cell · doi:10.1016/j.cell.2019.05.031 · Cited by 15,453
Fast, sensitive and accurate integration of single-cell data with Harmony
Korsunsky, I., Millard, N., Fan, J., Slowikowski, K., Zhang, F., Wei, K., Baglaenko, Y., Brenner, M., Loh, P.-R., & Raychaudhuri, S. (2019) · Nature Methods · doi:10.1038/s41592-019-0619-0 · Cited by 10,488
Complex heatmaps reveal patterns and correlations in multidimensional genomic data
Gu, Z., Eils, R., & Schlesner, M. (2016) · Bioinformatics · doi:10.1093/bioinformatics/btw313 · Cited by 10,037
QuPath: Open source software for digital pathology image analysis
Bankhead, P., Loughrey, M. B., Fernández, J. A., Dombrowski, Y., McArt, D. G., Dunne, P. D., McQuaid, S., Gray, R. T., Murray, L. J., Coleman, H. G., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-17204-5 · Cited by 8,908
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971
Self-citationDissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq
Tirosh, I., Izar, B., Prakadan, S. M., Wadsworth, M. H., Treacy, D., Trombetta, J. J., Rotem, A., Rodman, C., Lian, C., Murphy, G., et al. (2016) · Science · doi:10.1126/science.aad0501 · Cited by 4,944
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Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration
Patani, R., Hardingham, G. E., & Liddelow, S. A. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00822-1 · Cited by 531
“…the reactive astrocyte substates that have been described following inflammatory insults are also induced by STAT3 8,50,95,97 ; however, well-powered scRNA-seq and snRNA-seq studies have uncovered several low-abundance, biologically important substates that are not under STAT3 control 50,56,141 .”
BackgroundMethodResultInfluentialSelf-citationMild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
Fernández-Castañeda, A., Lu, P., Geraghty, A. C., Song, E., Lee, M.-H., Wood, J., O’Dea, M. R., Dutton, S., Shamardani, K., Nwangwu, K., et al. (2022) · Cell · doi:10.1016/j.cell.2022.06.008 · Cited by 521
Self-citationMathys, H., Peng, Z., Boix, C. A., Victor, M. B., Leary, N., Babu, S., Abdelhady, G., Jiang, X., Ng, A. P., Ghafari, K., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.039 · Cited by 495
“To validate our differential expression results, we compared them to those of previously published snRNA-seq studies of Alzheimer’s disease 14,15,23,24 and found a significant positive correlation for gene expression changes across multiple cell types, with particularly high concordance between our…”
ResultAstrocytes in human central nervous system diseases: a frontier for new therapies
Verkhratsky, A., Butt, A., Li, B., Illes, P., Zorec, R., Semyanov, A., Tang, Y., & Sofroniew, M. V. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01628-9 · Cited by 428
“Transcriptome analyses suggest both gain and loss of functions in astrocytes in AD mouse models, with downregulation of genes associated with neuronal support and upregulation of inflammation related genes.(613,614) Astrocytes in AD animal models, as well as astrocytes differentiated from stem cells isolated from AD p…”
BackgroundAstrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders
Brandebura, A. N., Paumier, A., Onur, T. S., & Allen, N. J. (2023) · Nature Reviews Neuroscience · doi:10.1038/s41583-022-00641-1 · Cited by 427
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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