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Cited by 223Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and Treatments

Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology

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Jiwaji, Zoeb, Tiwari, Sachin S., Avilés-Reyes, Rolando X., Hooley, Monique, Hampton, David, Torvell, Megan, Johnson, Delinda A., McQueen, Jamie +23 more·2022·Nature Communications
DOI 10.1038/s41467-021-27702-wPMC PMC8748982
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Abstract

Alzheimer’s disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPT P301S tauopathy mice revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct but overlapping signatures found in human post-mortem AD astrocytes. Both Aß and Tau pathology induced an astrocyte signature involving repression of bioenergetic and translation machinery, and induction of inflammation pathways plus protein degradation/proteostasis genes, the latter enriched in targets of inflammatory mediator Spi1 and stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 expression induced a reactive phenotype which recapitulated elements of this proteostasis signature, reduced Aß deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, Aß and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.

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  • Aβ and pTau have a synergistic effect on the astrocyte transcriptome.

    “further suggesting a synergistic effect of Aβ and pTau on the astrocyte transcriptome5”

    From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [5]

    The Results section, “A core signature of astrocytic genes regulated by both Tau and Aß pathology” (Fig. 3A; page not provided), reports overlapping astrocyte gene-expression changes in separate tauopathy and amyloidopathy mouse models. It does not establish that Aß and phosphorylated tau act synergistically on the astrocyte transcriptome. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Microglial activation or inflammatory insults induce astrocytes into a reactive state, which can have both neuroprotective and neurotoxic effects.

    “Microglial activation or inflammatory insults induce astrocytes into a reactive state, which can have both neuroprotective and neurotoxic effects [17, 183–185].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [185]

  • Previous transcriptomic studies comparing AD mouse models have reported similarities and differences in astrocyte responses to Aβ plaques versus pTau NFTs.

    “Previous transcriptomic studies comparing AD mouse models have reported similarities and differences in astrocyte responses to Aβ plaques versus pTau NFTs5,7,33.”

    From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [5]

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References 88 · Cited by 223

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Authors
Jiwaji, Z., Tiwari, S. S., Avilés-Reyes, R. X., Hooley, M., Hampton, D., Torvell, M., Johnson, D. A., McQueen, J., Baxter, P., Sabari-Sankar, K., Qiu, J., He, X., Fowler, J., Febery, J., Gregory, J., Rose, J., Tulloch, J., Loan, J., Story, D., McDade, K., Smith, A. M., Greer, P., Ball, M., Kind, P. C., Matthews, P. M., Smith, C., Dando, O., Spires-Jones, T. L., Johnson, J. A., Chandran, S., & Hardingham, G. E.
Affiliations
  • UK Dementia Research Institute (GB)
  • University of Wisconsin–Madison (US)
  • University of Edinburgh (GB)
  • Hammersmith Hospital (GB)
Corresponding author
  • Johnson, Jeffrey A.
  • Chandran, Siddharthan
  • Hardingham, Giles E.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-01-10
Volume
13
Issue
1
Pages
135-135
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-27702-w
PMC
PMC8748982
OpenAlex
W4205976963
Cited by
223
References
88
Citations by year
2026: 33 · 2025: 39 · 2024: 58 · 2023: 69 · 2022: 24
FWCI
30.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Funders
RCUK | Medical Research Council (MC_PC_17113)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
reactive astrocytes, Alzheimer's disease, tau pathology, amyloid-beta, astrocyte transcriptome, Nrf2, PU.1, proteostasis, neuroinflammation, bioenergetics, translation machinery, neurodegeneration, cognitive impairment
MeSH terms
Neuroprotection, Proteostasis, Proto-Oncogene Protein Spi-1, Alzheimer Disease, Animals, Astrocytes, Brain, Disease Models, Animal, Female, Gene Expression Regulation, Homozygote, Humans, Mice, Transgenic, Phenotype, Phosphorylation, Proto-Oncogene Proteins, Signal Transduction, Trans-Activators, Amyloid beta-Protein Precursor, tau Proteins, Gene Expression Profiling, NF-E2-Related Factor 2, Mice

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