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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Transcriptomic studies have shown changes in microglia, astrocytes, and oligodendrocytes in human Alzheimer's disease tissue.
“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]
The Abstract and Introduction report transcriptomic changes in astrocytes and oligodendrocytes from human AD tissue. This paper does not report corresponding changes in microglia, so it supports only part of the claim attributed to the joint citation. No page numbers are available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThis astrocyte subcluster was enriched for genes involved in extracellular matrix organization, metabolic support, and inflammatory modulation.
“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]
In Results, under “Transcriptionally distinct astrocyte subtypes are independent of disease state” (page unavailable), the paper reports extracellular-matrix-related transcripts in astrocyte clusters 2 and 5. Under “Astrocytes have both putative gain and loss of function in Alzheimer’s disease” (page unavailable), it reports lipid-storage and fatty-acid-oxidation pathways in cluster 5, but does not establish that this cluster provides metabolic support. The cited source is attached to the extracellular-matrix and metabolic-support portions of the sentence, not the separately cited inflammatory-modulation portion. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe snRNA-seq dataset contains over 100,000 astrocyte nuclei in each brain region with ≈6,000 average total reads and ≈2,500 average total genes detected, which is orders of magnitude higher than previous studies.
“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]
The Results section reports that Sadick et al. captured 41,340 astrocyte nuclei across their final donor cohort, supporting its use as a comparison with a larger dataset. It does not establish that more than 100,000 nuclei per brain region is orders of magnitude higher than its dataset. The STAR METHODS section gives median counts and detected features for all nuclei, not the citing sentence’s average reads and genes for astrocytes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe exhausted phase may have confounded previous studies that compared only control and severe AD donors or grouped late- and end-stage donors (Braak stage V/VI) together.
“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]
The Results section (‘Defining a well-controlled patient cohort’; page unavailable) says the paper compared non-symptomatic donors with AD donors and classified the latter as having moderate or severe pathology. It does not say the comparison included only severe AD donors, document a Braak V/VI grouping, or identify an ‘exhausted phase’ as a confounder. The possible confounding is the citing authors’ speculation, but the specific description of this study’s donor groups is only partly supported. (LLM, conf=0.81)
Experimental — accuracy not yet measuredA snRNA-seq study in human AD reported downregulation of synaptic cell adhesion-related gene expression and enrichment terms in an oligodendrocyte cluster.
“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]
The study's sample sizes are similar to those reported in previous publications.
“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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Novel Phosphodiesterase Inhibitors for Cognitive Improvement in Alzheimer’s Disease
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A rapid and cost-effective method for genotyping apolipoprotein E gene polymorphism
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N-Cadherin Is Involved in Axon-Oligodendrocyte Contact and Myelination
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Regulator of Cell Cycle (RGCC) Expression during the Progression of Alzheimer's Disease
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The Emerging Role of Mechanics in Synapse Formation and Plasticity
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Don't forget astrocytes when targeting Alzheimer's disease
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Self-citationggdist: Visualizations of Distributions and Uncertainty
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DISC1 regulates cell–cell adhesion, cell–matrix adhesion and neurite outgrowth
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SALM/Lrfn Family Synaptic Adhesion Molecules
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Galantamine attenuates amyloid-β deposition and astrocyte activation in APP/PS1 transgenic mice
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Targeted quantitative analysis of synaptic proteins in Alzheimer’s disease brain
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The promise of stem cells in the therapy of Alzheimer’s disease
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Blood transcriptomic biomarker as a surrogate of ischemic brain gene expression
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Dual-Specificity Phosphatases in Neuroblastoma Cell Growth and Differentiation
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DISC1 regulates N-cadherin and β1-integrin expression in neurons
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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 · see citing works
“…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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy
Zheng, Q., & Wang, X. (2024) · Protein & Cell · doi:10.1093/procel/pwae026 · Cited by 454 · see citing works
The neurobiology of long COVID
Monje, M., & Iwasaki, A. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.006 · Cited by 415 · see citing works
“Neuroinflammatory reactive astrocytes across a range of cellular states (Hasel et al., 2021; Sadick et al., 2022) can induce further pathophysiology, with certain states of reactive astrocytes inducing cell death of oligodendrocytes and of susceptible neurons (Guttenplan et al., 2021; Liddelow et…”
Ageing and rejuvenation of tissue stem cells and their niches
Brunet, A., Goodell, M. A., & Rando, T. A. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00510-w · Cited by 407 · see citing works
Neuroinflammation: An astrocyte perspective
Lee, H., Lee, J.-H., Flausino, L. E., & Quintana, F. J. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adi7828 · Cited by 241 · see citing works
Three-Dimensional Cell Cultures: The Bridge between In Vitro and In Vivo Models
Urzì, O., Gasparro, R., Costanzo, E., Luca, A. D., Giavaresi, G., Fontana, S., & Alessandro, R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512046 · Cited by 247 · see citing works
Cellular communities reveal trajectories of brain ageing and Alzheimer’s disease
Green, G. S., Fujita, M., Yang, H.-S., Taga, M., Cain, A., McCabe, C., Comandante-Lou, N., White, C. C., Schmidtner, A. K., Zeng, L., et al. (2024) · Nature · doi:10.1038/s41586-024-07871-6 · Cited by 204 · see citing works
Lipid-accumulated reactive astrocytes promote disease progression in epilepsy
Chen, Z.-P., Wang, S., Zhao, X., Fang, W., Wang, Z., Ye, H., Wang, M.-J., Ke, L., Huang, T., Lv, P., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01288-6 · Cited by 214 · see citing works
Microglia regulation of central nervous system myelin health and regeneration
Kent, S. A., & Miron, V. E. (2024) · Nature Reviews Immunology · doi:10.1038/s41577-023-00907-4 · Cited by 183 · see citing works
“Accordingly, oligodendrocytes undergo robust transcriptional changes in models of AD and early on in human AD 27–30 .”
InfluentialAbsence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice
Kiani Shabestari, S., Morabito, S., Danhash, E. P., McQuade, A., Sanchez, J. R., Miyoshi, E., Chadarevian, J. P., Claes, C., Coburn, M. A., Hasselmann, J., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110961 · Cited by 167 · see citing works
“Astrocytes can also respond to amyloid plaques and microglial-astrocytic crosstalk plays an important role in AD pathogenesis (Liddelow et al., 2017; Sadick et al., 2022).”
Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease
Serrano-Pozo, A., Li, H., Li, Z., Muñoz-Castro, C., Jaisa-aad, M., Healey, M. A., Welikovitch, L. A., Jayakumar, R., Bryant, A. G., Noori, A., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01791-4 · Cited by 140 · see citing works
The interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing
Liu, Y., Tan, Y., Zhang, Z., Yi, M., Zhu, L., & Peng, W. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00397-x · Cited by 144 · see citing works
“The subsequent development of spatial transcriptomic sequencing allows direct mapping of the functions of cells in different parts of the body [258].”
BackgroundMallach, A., Zielonka, M., van Lieshout, V., An, Y., Khoo, J. H., Vanheusden, M., Chen, W.-T., Moechars, D., Arancibia-Carcamo, I. L., Fiers, M., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114216 · Cited by 135 · see citing works
“Other studies have shown that astrocytes display region-specific differences, both in terms of their phenotype 19 and their functions, including calcium signaling.”
Inflammatory aspects of Alzheimer’s disease
Lucena, P. B., & Heneka, M. T. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02790-2 · Cited by 143 · see citing works
Caglayan, E., Liu, Y., & Konopka, G. (2022) · Neuron · doi:10.1016/j.neuron.2022.09.010 · Cited by 123 · see citing works
Molecular and metabolic heterogeneity of astrocytes and microglia
Hasel, P., Aisenberg, W. H., Bennett, F. C., & Liddelow, S. A. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.03.006 · Cited by 129 · see citing works
Self-citationRevolutionizing Neurocare: Biomimetic Nanodelivery Via Cell Membranes
Liao, J., Gong, L., Xu, Q., Wang, J., Yang, Y., Zhang, S., Dong, J., Lin, K., Liang, Z., Sun, Y., et al. (2024) · Advanced Materials · doi:10.1002/adma.202402445 · Cited by 123 · see citing works
A brain cell atlas integrating single-cell transcriptomes across human brain regions
Chen, X., Huang, Y., Huang, L., Huang, Z., Hao, Z.-Z., Xu, L., Xu, N., Li, Z., Mou, Y., Ye, M., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-03150-z · Cited by 117 · see citing works
Kaji, S., Berghoff, S. A., Spieth, L., Schlaphoff, L., Sasmita, A. O., Vitale, S., Büschgens, L., Kedia, S., Zirngibl, M., Nazarenko, T., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.09.014 · Cited by 104 · see citing works
Pathogenesis of Alzheimer's disease: Involvement of the choroid plexus
Čarná, M. E., Onyango, I. G., Katina, S., Holub, D., Novotný, J., Nezvedová, M., Jha, D., Nedelská, Z., Lacovich, V., Vyvere, T. V., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.12970 · Cited by 96 · see citing works
Axonal energy metabolism, and the effects in aging and neurodegenerative diseases
Yang, S., Park, J. H., & Lu, H.-C. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00634-3 · Cited by 94 · see citing works
An astrocyte BMAL1-BAG3 axis protects against alpha-synuclein and tau pathology
Sheehan, P. W., Nadarajah, C. J., Kanan, M. F., Patterson, J. N., Novotny, B. C., Lawrence, J. H., King, M. W., Brase, L., Inman, C. E., Yuede, C. M., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.05.006 · Cited by 89 · see citing works
Revisiting the critical roles of reactive astrocytes in neurodegeneration
Qian, K., Jiang, X., Liu, Z., Zhang, J., Fu, P. F., Su, Y., Brazhe, N. A., Liu, D., & Zhu, L. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02061-8 · Cited by 94 · see citing works
“…snRNA-seq analyses, we will discuss the identi fi cation, de fi nition and functions of astrocyte subsets in Alzheimer ’ s disease (AD) [11, 14 – 16], Parkinson ’ s disease (PD) [17 – 19], Huntington ’ s disease (HD) [20 – 24], multiple sclerosis (MS) [6, 7, 25 – 28] and amyotrophic lateral…”
BackgroundEmerging roles of oligodendrocyte precursor cells in neural circuit development and remodeling
Buchanan, J., da Costa, N. M., & Cheadle, L. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.05.007 · Cited by 88 · see citing works
Anderson, A. G., Rogers, B. B., Loupe, J. M., Rodriguez-Nunez, I., Roberts, S. C., White, L. M., Brazell, J. N., Bunney, W. E., Bunney, B. G., Watson, S. J., et al. (2023) · Cell Genomics · doi:10.1016/j.xgen.2023.100263 · Cited by 82 · see citing works
The role of astrocytic α7 nicotinic acetylcholine receptors in Alzheimer disease
Fontana, I. C., Kumar, A., & Nordberg, A. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00792-4 · Cited by 86 · see citing works
Qian, Z., Qin, J., Lai, Y., Zhang, C., & Zhang, X. (2023) · Biomolecules · doi:10.3390/biom13040692 · Cited by 79 · see citing works
The roles of microglia and astrocytes in neuroinflammation of Alzheimer’s disease
Han, J., Zhang, Z., Zhang, P., Yu, Q., Cheng, Q., Lu, Z., & Zong, S. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1575453 · Cited by 87 · see citing works
Reactive astrogliosis in the era of single-cell transcriptomics
Matusova, Z., Hol, E. M., Pekny, M., Kubista, M., & Valihrach, L. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1173200 · Cited by 72 · see citing works
“Although astrocytes show some common features in response to different pathological stimuli, their heterogeneity is far more complex and dynamic than previously thought (Stahlberg et al., 2011; Rusnakova et al., 2013; Orre et al., 2014; Pekny et al., 2019; Batiuk et al., 2020; Bayraktar et al., 2020; Gomes et al., 202…”
BackgroundWhite matter injury across neurodegenerative disease
Festa, L. K., Grinspan, J. B., & Jordan‐Sciutto, K. L. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.11.003 · Cited by 71 · see citing works
White matter damage and degeneration in traumatic brain injury.
Armstrong, R. C., Sullivan, G. M., Perl, D. P., Rosarda, J. D., & Radomski, K. L. (2024) · Trends in Neurosciences · doi:10.1016/j.tins.2024.07.003 · Cited by 62 · see citing works
Emerging roles of astrocytes as immune effectors in the central nervous system
Fisher, T. M., & Liddelow, S. A. (2024) · Trends in Immunology · doi:10.1016/j.it.2024.08.008 · Cited by 69 · see citing works
Self-citationXie, L., Wu, Q., Li, K., Khan, M. A. S., Zhang, A., Sinha, B., Li, S., Chang, S. L., Brody, D. L., Grinstaff, M. W., et al. (2024) · Aging and Disease · doi:10.14336/ad.2024.0134 · Cited by 63 · see citing works
“Interestingly, astrocytic degeneration is present in a subset of AD human brain samples [4].”
BackgroundThe impact of astrocytic NF-κB on healthy and Alzheimer’s disease brains
Huat, T. J., Camats‐Perna, J., Newcombe, E. A., Onraet, T., Campbell, D., Sucic, J. T., Martini, A. C., Forner, S., Mirzaei, M., Poon, W. W., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-65248-1 · Cited by 64 · see citing works
Cell type-specific changes identified by single-cell transcriptomics in Alzheimer’s disease
Luquez, T., Gaur, P., Kosater, I. M., Lam, M., Lee, D. I., Mares, J. A., Paryani, F., Yadav, A., & Menon, V. (2022) · Genome Medicine · doi:10.1186/s13073-022-01136-5 · Cited by 59 · see citing works
“[49] report a putative duality in the astrocytic function that can also be observed in other datasets, where both loss and gain of function signatures coincide in the same cluster.”
BackgroundInfluentialForet, M. K., Orciani, C., Welikovitch, L. A., Huang, C., Cuello, A. C., & Carmo, S. D. (2024) · Communications Biology · doi:10.1038/s42003-024-06552-4 · Cited by 62 · see citing works
“Increased expression of Fancc has been reported in astrocyte-and oligodendrocyte-enriched fractions of AD brains at the single-nuclei level 113 .”
Chandra, S., Di Meco, A., Dodiya, H. B., Popovic, J., Cuddy, L. K., Weigle, I. Q., Zhang, X., Sadleir, K., Sisodia, S. S., & Vassar, R. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00635-2 · Cited by 58 · see citing works
“of male APPPS1‐21 mice Astrocytes change their morphology and upregulate complement component C3 expression in the context of inflammatory stimuli, including Aβ deposits [11, 17, 18, 58, 60, 63].”
BackgroundModulating mTOR-dependent astrocyte substate transitions to alleviate neurodegeneration
Zhang, L., Xu, Z., Jia, Z., Cai, S., Wu, Q., Liu, X., Hu, X., Bai, T., Chen, Y., Li, T., et al. (2025) · Nature Aging · doi:10.1038/s43587-024-00792-z · Cited by 59 · see citing works
“Furthermore, oligodendrocytes, previously considered functionally homogeneous, have also been found to exhibit molecular and functional heterogeneity in different stages of maturation and in various diseases 13,16,17 .”
Schartz, N. D., Liang, H. Y., Carvalho, K., Chu, S., Mendoza‐Arvilla, A., Petrisko, T. J., Gómez-Arboledas, Á., Mortazavi, A., & Tenner, A. J. (2024) · Nature Communications · doi:10.1038/s41467-024-51163-6 · Cited by 64 · see citing works
Rajani, R. M., Ellingford, R., Hellmuth, M., Harris, S. S., Taso, O. S., Graykowski, D., Lam, F. K. W., Arber, C., Fertan, E., Danial, J. S. H., et al. (2024) · PLOS Biology · doi:10.1371/journal.pbio.3002727 · Cited by 57 · see citing works
“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] and in mouse models of AD [7,8].”
BackgroundLabarta-Bajo, L., & Allen, N. J. (2025) · Neuron · doi:10.1016/j.neuron.2024.12.010 · Cited by 58 · see citing works
Reactive Astrocytes and Emerging Roles in Central Nervous System (CNS) Disorders
Liddelow, S. A., Olsen, M. L., & Sofroniew, M. V. (2024) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041356 · Cited by 55 · see citing works
Self-citationSingle-Cell RNA Sequencing Technology Landscape in 2023
Qu, H., Kao, C., & Hakonarson, H. H. (2023) · Stem Cells · doi:10.1093/stmcls/sxad077 · Cited by 58 · see citing works
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“We revealed perturbations in key myelin regulators, such as OPALIN , CNP and MAG , across oligo-dendrocyte clusters but in these cells only, as opposed to AD where myelination-related changes were present across multiple cell types 35,55 .”
Neurodegeneration cell per cell
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“117,118 In PD, enriched astrocytic cell-state markers have been identified as CD44/S100A6, VIM/LHX2 and CYP4F12, while astrocytic populations marked by GJB6/OXTR and CYP4F12 were depleted.”
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Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins
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APOE genotype determines cell-type-specific pathological landscape of Alzheimer’s disease
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Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics
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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 · see citing works
“…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 44 · see citing works
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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
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Astrocytes: The Stars in Neurodegeneration?
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“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
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“(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 · see citing works
“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 36 · see citing works
Proteomic profiling of interferon‐responsive reactive astrocytes in rodent and human
Prakash, P., Erdjument‐Bromage, H., O’Dea, M. R., Munson, C. N., Labib, D., Fossati, V., Neubert, T. A., & Liddelow, S. A. (2023) · Glia · doi:10.1002/glia.24494 · Cited by 38 · see citing works
“…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 36 · see citing works
“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 36 · see citing works
Repeated head trauma causes neuron loss and inflammation in young athletes
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“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
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Oligodendrocyte pathology in Huntington’s disease: from mechanisms to therapeutics
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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 · see citing works
“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 · see citing works
“44 This underrepresentation may be due to the preferential loss of astrocytes during preparation, likely because of their distinct biochemical and biophysical properties.”
Davis, N., Taylor, B., Abelleira, L. E., Karimian‐Marnani, N., Aleksynas, R., Syed, N., Giovanni, S. D., Palmisano, I., & Sastre, M. (2024) · The FASEB Journal · doi:10.1096/fj.202301762rr · Cited by 30 · see citing works
C9orf72 hexanucleotide repeat expansions impair microglial response in ALS
Masrori, P., Bijnens, B., Fumagalli, L., Davie, K., Poovathingal, S. K., Meese, T. S., Storm, A., Hersmus, N., Fazal, R., van den Biggelaar, D., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02075-1 · Cited by 30 · see citing works
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 · see citing works
Heterogeneity of Astrocyte Reactivity
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Astrocytes regulate neuronal network activity by mediating synapse remodeling
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Astrocyte diversity and subtypes: aligning transcriptomics with multimodal perspectives
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“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 27 · see citing works
“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 27 · see citing works
“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 29 · see citing works
“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 · see citing works
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 · see citing works
“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 25 · see citing works
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 · see citing works
Self-citationZhang, Y., Li, T., Wang, G., & Ma, Y. (2024) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-024-01499-w · Cited by 25 · see citing works
“…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
- 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 · 2021: 1 · 2012: 1
- 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
- Health Sciences › Medicine › Physiology › 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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