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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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“On the other hand, genes linked to immune ODs (ImOLs) [90] and Int6 [89] phenotypes often had ALS-increased expression and included several increased DEGs such as APOC1 , APOE , MSR1 and NRP2 (Figure S28F–”
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“This approach has been successfully applied to reveal nuanced cell-type-specific responses in neurological diseases such as multiple sclerosis and Alzheimer’s disease [18], but its application to the study of the brain-electrode interface remains limited.”
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“Whereby these cells undergo both gains and losses of functions that are dependent on their given subtype and regional pathogenic load (Sadick et al., 2022).”
BackgroundResearch progress on humoral biomarkers of Alzheimer’s disease: A review
Zhang, H., Fu, X., Yang, M., Song, X., Li, M., & Wang, X. (2024) · Medicine · doi:10.1097/md.0000000000038978 · Cited by 4
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Astrocytic AEG-1 drives neuroinflammation and enhances seizure susceptibility
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“In the near future, new pathogenic mechanisms will likely be unraveled at the molecular and cell level, thanks to the connectome, interactome and metabolome approaches currently developed in PD [417–424], AD [121,425–429], HD [430] and MS [400].”
Yuan, X., Li, W., Liu, Q., Ou, Y., Li, J., Yan, Q., & Zhang, P. (2024) · Cellular and molecular neurobiology · doi:10.1007/s10571-024-01524-y · Cited by 2
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Glia in Neurodegenerative DiseasePreprint
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Systematic review and meta-analysis of bulk RNAseq studies in human Alzheimer’s disease brain tissuePreprint
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“73 Other hits include genes involved in growth factor signaling such as FSTL1 and TGFBR2 .”
The roles of microglia and astrocytes in inflammasomes and neurological disorders
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“66,107 In our study, TDP-43 depletion resulted in elevated expression of immune-related genes in oligodendrocytes, an effect that became more pronounced after 6 months of TDP-43 depletion.”
scTWAS: a powerful statistical framework for single-cell transcriptome-wide association studies
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Histopathologic Findings and Knowledge Gaps in Glaucomatous Neurodegeneration
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“…future research directions is to integrate various spatial and single-cell sequencing techniques to understand the role of non-neuronal cells in brain development, diseases, and evolution (Armand et al., 2021; Park et al., 2023; Piwecka et al., 2023; Sadick et al., 2022; van Bruggen et al., 2017).”
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“Examples of both positive and negative selection can be found in the literature for many types of glia (e.g., Gerrits et al., 2021; Nott et al., 2019; Ochocka et al., 2021; Prater et al., 2023; Sadick et al., 2022; Schroeter et al., 2021; Wei et al., 2023; Yang et al., 2022).”
Multilayer Analysis of RNA Sequencing Data in Alzheimer’s Disease to Unravel Molecular Mysteries
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Morrissey, Z. D., Kumar, P., Phan, T., Maienschein‐Cline, M., Leow, A., & Lazarov, O. (2025) · Frontiers in Dementia · doi:10.3389/frdem.2025.1546433 · Cited by 2
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“Marker genes for cell types were selected based on previous publications [42,47,55].”
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Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric AßPreprint
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MiR-302-Induced anti-aging neural stem cells enhance cognitive function and extend lifespanPreprint
Li, Y., Sun, J., Zheng, Y., Xu, T., Zhang, Y., & Wang, Y. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.13.528232 · Cited by 2
“, APOE) impair astrocytes and microglia, which in turn can alter NSCs function (43, 44).”
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Single-cell Data Unveil the Multifaceted Role of LRP1 in Alzheimer’s Disease PathogenesisPreprint
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Integrative analysis reveals generalizable human neurodegenerative disease-associated glial statesPreprint
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Single-cell omics and heterogeneity of neuroglial cells
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Roles of Glia in Synapse Nano-organization
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Oligodendrocytes at the crossroads: Central players and interactive partners in white matter aging
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Decoding Alzheimer's Disease One Cell Class at a Time
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“This led to the identification of nine astrocyte subclasses with unique transcriptomic signa - tures (Sadick et al. 2022 ), with some level of overlap with prior works (Grubman et al. 2019; Mathys et al. 2019; Zhou et al. 2020 ).”
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Enhancer dynamics and cellular architecture in the human spinal cord
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“Although previous snRNA-seq studies have identified distinct cell populations and altered pathways in AD, 29,123–125 they lack the spatial resolution necessary to capture microenvironment-specific changes, a key feature AD/CAA mixed pathology.”
InfluentialSingle-nucleus brain transcriptomics reveals microglia dysfunction in multiple system atrophy
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“Importantly, snRNA-seq has been applied to postmortem brain samples of Alzheimer ’ s disease and revealed novel molecular mechanisms that dramatically improved our understanding of disease pathogenesis 14 – 17 .”
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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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