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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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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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