Disease-associated astrocytes in Alzheimer’s disease and aging
Open accessAbstract
The role of non-neuronal cells in Alzheimer's disease progression has not been fully elucidated. Using single-nucleus RNA sequencing, we identified a population of disease-associated astrocytes in an Alzheimer's disease mouse model. These disease-associated astrocytes appeared at early disease stages and increased in abundance with disease progression. We discovered that similar astrocytes appeared in aged wild-type mice and in aging human brains, suggesting their linkage to genetic and age-related factors.
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Astrocyte subcluster 3 are homeostatic astrocytes and astrocyte subclusters 5 and 7 are disease-associated astrocytes (DAAs), with upregulation of Gfap, Aqp4, Ctsb, Vim, Serpina3a, C4b and Cd9 expression.
“identified astrocyte subcluster 3 as homeostatic astrocytes and astrocyte subclusters 5 and 7 as disease-associated astrocytes (DAAs), with upregulation of Gfap, Aqp4, Ctsb, Vim, Serpina3a, C4b and Cd9 expression”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [62]
The passage describing the six subclusters (labeled Abstract in our copy) identifies clusters 1 and 2 as homeostatic and cluster 4 as DAAs. It identifies clusters 3 and 5 as intermediate states; there is no cluster 7 in that six-cluster scheme. The same section names Serpina3n, rather than Serpina3a, among DAA-upregulated genes. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredPrevious transcriptomic studies have revealed widespread changes in cell state in specific cell types with age, with many highlighting increased inflammation as a key aspect of brain aging.
“Previous transcriptomic studies have revealed widespread changes in cell state in specific cell types with age, with many of these studies highlighting a role for increased inflammation as a key aspect of brain aging.17–20,25–30”
From Molecular and spatial signatures of mouse brain aging at single-cell resolution (2023) · cites this paper as [27]
The paper’s Abstract (page unavailable) reports an age-related change in astrocyte state: DAA-like cells emerge in older wild-type mice and are found in aging human brains. It also reports inflammatory astrocyte signatures, but the comparison is Alzheimer’s disease versus wild-type mice; it does not establish increased inflammation as a feature of normal brain aging. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMicroglial and astrocytic activation has also been reported in aged rodent and human brains.
“Microglial and astrocytic activation has also been reported in aged rodent and human brains”
From Molecular and spatial signatures of mouse brain aging at single-cell resolution (2023) · cites this paper as [27]
The Abstract (page unavailable) reports DAA-like astrocytes in aging wild-type mice and aging human brains. It also reports that microglia increased with age in Alzheimer’s-model mice, but does not establish microglial activation in normally aging rodents or humans. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSingle-cell and single-nucleus RNA sequencing studies have identified multiple disease-associated glial subtypes with distinct transcriptional states and selectively vulnerable neuronal populations in amyloidosis or tauopathy models.
“These studies have identified multiple disease‐associated glial subtypes with distinct transcriptional states and selectively vulnerable neuronal populations in amyloidosis models 16 , 17 , 18 or tauopathy models. 19 , 20 , 21”
From Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses (2026) · cites this paper as [18]
The Results passages in our copy (section labeled Abstract; page unavailable) identify disease-associated astrocytes with distinct transcriptional states in 5xFAD mice and report changes in disease-associated microglia. They also report a reduced proportion of recently activated pyramidal neurons, but do not establish that a neuronal population is selectively vulnerable. This paper studies an amyloidosis model, not a tauopathy model. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn the early epoch, donors had sparse Aβ plaques (albeit increasing in size) and pTau+ tangle-bearing neurons, accompanied by early increases in inflammatory or reactive microglial and astrocytic states and associated gene expression changes in relevant inflammatory and plaque-induced genes.
“In the early epoch, donors had sparse Aβ plaques (albeit increasing in size) and pTau+ tangle-bearing neurons, accompanied by early increases in inflammatory or reactive microglial7 and astrocytic states69 and associated gene expression changes in relevant inflammatory85 and plaque-induced genes (Fig. 8b).”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [69]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
In the study of AD transgenic and wild-type mice, homeostatic astrocytes were predominant in healthy mice, whereas disease-associated astrocytes were unique to AD mice.
“In this study, ‘homeostatic astrocytes’ were predominant in healthy mice, whereas ‘disease-associated astrocytes’ were unique to AD mice.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [78]
The paper reports a homeostatic Gfap-low state in wild-type mice and a disease-associated astrocyte state observed only in AD mice in its initial comparison (Abstract; no page given). But its age-series analysis also finds DAA-like cells in older wild-type mice, so the unqualified claim that they were unique to AD mice overstates the finding. (LLM, conf=0.87)
Experimental — accuracy not yet measuredTwo new names have recently been coined to describe the extremes of six astrocytic transcriptional clusters detected by snRNAseq in the hippocampus of AD transgenic and wild-type mice.
“Nonetheless, two new names have recently been coined to describe the extremes of six astrocytic transcriptional clusters detected by snRNAseq in the hippocampus of AD transgenic and wild-type mice78.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [78]
The passage on astrocyte states reports six transcriptional sub-clusters from single-nucleus RNA-seq of WT and 5xFAD mouse hippocampi. It says the authors coined “Disease-Associated Astrocytes” for cluster 4, but does not say they coined two new names for the extremes: it describes Gfap-low and Gfap-high states as consistent with previous observations, and the DAA state as an additional state. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe DAAs and DAMs have transcriptomic profiles similar to those previously reported in brains of patients with AD and mouse models.
“The DAAs and DAMs have transcriptomic profiles similar to those reported previously in brains of patients with AD and mouse models62,63.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [62]
The paper reports overlap between DAA genes and a previously described DAM signature, and Extended Data Figure 9 compares mouse DAA profiles with astrocytes from human AD and non-AD brains. The Methods state that the DAM signature came from prior literature; this paper does not establish that both DAA and DAM profiles resemble profiles previously reported in human AD brains. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDEGs associated with the E4 to E2 switch strongly reflected several APOE-associated and AD-associated gene lists, particularly LOAD genes from publicly available human transcriptomic datasets.
“Finally, the DEGs associated with the E4 to E2 switch also strongly reflected several APOE-associated and AD-associated gene lists, particularly the late-onset AD (LOAD) genes identified in and merged from publicly available human transcriptomic datasets (Fig. 3i)25–28.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [27]
Cluster 26 overlapped gene sets with previously reported reactive glial substates, including DAM1, DAM2, DAA, PIGs, and IRRAs.
“we found overlapping gene sets compared to previously reported, biologically defined reactive glial substates. This included integration with differentially expressed genes (DEGs) from disease associated microglia, both early (DAM1) and late (DAM2),25 disease associated astrocytes (DAA),26 plaque-induced genes (PIGs),27 and our previously identified interferon-responsive reactive astrocytes (IRRAs”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [26]
These Gq-DREADD activated astrocytes did not show the transcriptional profile of other recently identified astrocyte subtypes such as PAN reactive, A1-specific, A2-specific, disease-associated astrocytes, or astrocytes seen in acute injury and chronic neurodegeneration.
“Furthermore, we also noticed that these Gq-DREADD activated astrocytes did not show the transcriptional profile of other, recently identified astrocyte subtypes such as PAN reactive, A1-specific, A2-specific, disease-associated astrocytes, or astrocytes seen in acute injury and chronic neurodegeneration (Supplementary Figure 2A-C) (Das et al., 2020;Habib et al., 2020;Liddelow et al., 2017).”
From Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia (2020) · cites this paper as Habib et al., 2020
Sc-8 astrocytes displayed an enrichment for gene signatures of Disease-associated astrocytes (DAA), reactive astrocytes linked to inflammatory state, and EAE astrocytes.
“Moreover, sc-8 astrocytes displayed an enrichment for gene signatures of Disease-associated astrocytes (DAA) identified in an AD mouse model42, reactive astrocytes linked to inflammatory state10, as well as EAE astrocytes43 (Fig. 4G).”
From Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease (2024) · cites this paper as [42]
Single-cell and single-nucleus RNAseq studies in mouse models and human brains of chronic neurodegenerative diseases have unraveled numerous stage-dependent transcriptomic states in HD, AD, and MS that do not clearly comply with A1-A2 profiles.
“For example, single-cell and single-nucleus RNAseq (scRNAseq and snRNAseq, respectively) studies in mouse models and human brains of chronic neurodegenerative diseases have unraveled numerous stage-dependent transcriptomic states in HD74, AD75,78, and MS40 that do not clearly comply with A1–A2 profiles.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [78]
ScRNAseq and snRNAseq are becoming established as valuable tools to gain insight into basal and reactive-astrocyte heterogeneity.
“ScRNAseq and snRNAseq are becoming established as valuable tools to gain insight into basal94 and reactive-astrocyte heterogeneity (Fig. 1e)40,78,95.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [78]
Astrocytes play a critical role in the pathophysiology of both DS and AD.
“Accumulating evidence has underscored the critical role of astrocytes in the pathophysiology of both DS (56) and AD (57).”
From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [57]
DAA pathway phenotypes are associated with AD.
“APOE4 derived iAstrocytes showed increased inflammatory protein expression including those associated with DAA pathway phenotypes in AD [42][43][44][45] .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [45]
Previous studies using transgenic mouse models of AD have identified various mechanisms that lead to synaptic impairment in AD, including the accumulation of soluble amyloid-beta, Tau hyperphosphorylation, loss of VGF signaling, and glial state dysregulation.
“For example, previous studies using transgenic mouse models of AD have identified various mechanisms that lead to synaptic impairment in AD, including the accumulation of soluble amyloid-beta, Tau hyperphosphorylation, loss of VGF signaling, and glial state dysregulation (e.g., the induction of disease-associated microglia and disease-associated astrocytes) (9, 23–30).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [28]
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“…early epoch, donors had sparse Aβ plaques (albeit increasing in size) and pTau + tangle-bearing neurons, accompanied by early increases in inflammatory or reactive microglial 7 and astrocytic states 69 and associated gene expression changes in relevant inflammatory 85 and plaque-induced genes (Fig.”
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Early Alzheimer’s disease pathology in human cortex involves transient cell states
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Diverse human astrocyte and microglial transcriptional responses to Alzheimer’s pathology
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“The disease associated astrocyte (DAA) expression signature defined in a mouse model [19] was represented in all astrocyte clusters other than Astro3 (Supplementary Table 16, online resource).”
BackgroundAPOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints
Yin, Z., Rosenzweig, N., Kleemann, K. L., Zhang, X., Brandão, W., Margeta, M. A., Schroeder, C., Sivanathan, K. N., Silveira, S., Gauthier, C., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01627-6 · Cited by 202 · see citing works
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Humphrey, J., Venkatesh, S., Hasan, R., Herb, J. T., de Paiva Lopes, K., Küçükali, F., Byrska-Bishop, M., Evani, U. S., Narzisi, G., Fagegaltier, D., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-022-01205-3 · Cited by 138 · see citing works
Multicellular communities are perturbed in the aging human brain and Alzheimer’s disease
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Self-citationAstrocyte 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
Joint single-cell measurements of nuclear proteins and RNA in vivo
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Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits
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The Many Faces of Astrocytes in Alzheimer's Disease
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Microglia and Astrocytes in Alzheimer’s Disease: Significance and Summary of Recent Advances
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Oligodendrocyte progenitor cells in Alzheimer's disease: from physiology to pathology
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Astrocyte-derived extracellular vesicles: A double-edged sword in central nervous system disorders
Zhao, S., Sheng, S., Wang, Y., Ding, L., Xu, X., Xia, X., & Zheng, J. C. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.02.027 · Cited by 90 · see citing works
The role of astrocytic α7 nicotinic acetylcholine receptors in Alzheimer disease
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Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation
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“39,40 Indeed, our Inpp5d knockdown exacerbated the plaque-induced Cluster 26 profile, which overlaps with previously reported reactive glial substates, including DEGs from both early and late DAM profiles, 25 and our previously identified IRRAs.”
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Extracellular vesicles (exosomes and ectosomes) play key roles in the pathology of brain diseases
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The Molecular Clock and Neurodegenerative Disease: A Stressful Time
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“INTRODUCTION Aging is one of the major risk factors for many diseases [1], and the development of methods to intervene in aging will significantly reduce the risk of a series of age-related diseases such as cardiovascular and cerebrovascular diseases [2, 3], cancer [4], and Alzheimer’s disease [5].”
BackgroundMulti-cellular communities are perturbed in the aging human brain and Alzheimer’s disease
Cain, A., Taga, M., McCabe, C., Green, G., Hekselman, I., White, C. C., Lee, D. I., Gaur, P., Rozenblatt-Rosen, O., Zhang, F., et al. (2020) · doi:10.1101/2020.12.22.424084 · Cited by 143 · see citing works
Self-citationZhou, Y., Xu, J., Hou, Y., Bekris, L., Leverenz, J. B., Pieper, A. A., Cummings, J., & Cheng, F. (2022) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1002/trc2.12350 · Cited by 39 · see citing works
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Uncovering Plaque-Glia Niches in Human Alzheimer’s Disease Brains Using Spatial Transcriptomics
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Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain
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Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex
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“…the transcriptomic profile of our chronically Gq-DREADD activated astrocytes with the transcriptomic profiles of astrocytes in recent publications, as well as with PAN-reactive, and A1 and A2 astrocytes (Supplementary Figure 2A-C) (Das et al., 2020; Habib et al., 2020; Liddelow et al., 2017).”
BackgroundInfluentialApoE expression across the CNS: Who, What, Where, When, and How (much)?
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APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology
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Human brain microRNAs exhibit cell-type specificity and age dependence
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- Authors
- Habib, N., McCabe, C., Medina, S., Varshavsky, M., Kitsberg, D., Dvir-Szternfeld, R., Green, G., Dionne, D., Nguyen, L., Marshall, J. L., Chen, F., Zhang, F., Kaplan, T., Regev, A., & Schwartz, M.
- Affiliations
- Broad Institute (US)
- Weizmann Institute of Science (IL)
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Habib, Naomi
- Regev, Aviv
- Schwartz, Michal
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2020-04-27
- Volume
- 23
- Issue
- 6
- Pages
- 701-706
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC9262034
- OpenAlex
- W3018541302
- Cited by
- 1,009
- References
- 37
- Citations by year
- 2026: 157 · 2025: 179 · 2024: 151 · 2023: 186 · 2022: 152 · 2021: 147 · 2020: 34 · 2012: 1
- FWCI
- 81.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (U19MH114821)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- Alzheimer's disease, brain aging, astrocytes, single-nucleus RNA sequencing, mouse models of Alzheimer's disease, non-neuronal cells, disease progression
- MeSH terms
- Aging, Alzheimer Disease, Animals, Astrocytes, Brain, Female, Hippocampus, Humans, Male, Mice, Transgenic, Amyloid beta-Protein Precursor, Disease Progression, Mice
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