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

Zoeb Jiwaji, Sachin S. Tiwari, Rolando X. Avilés-Reyes, Monique Hooley, David Hampton, Megan Torvell, Delinda A. Johnson, Jamie McQueen, Paul Baxter, Kayalvizhi Sabari-Sankar, Jing Qiu, Xin He, Jill Fowler, James Febery, Jenna Gregory, Jamie Rose, Jane Tulloch, Jamie Loan, David Story, Karina McDadeAmy M. Smith, Peta Greer, Matthew Ball, Peter C. Kind, Paul M. Matthews, Colin Smith, Owen Dando, Tara L. Spires-Jones, Jeffrey A. Johnson* (Corresponding Author), Siddharthan Chandran* (Corresponding Author), Giles E. Hardingham* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


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.
Original languageEnglish
Article number135
Number of pages23
JournalNature Communications
Issue number1
Publication statusPublished - 10 Jan 2022


  • Alzheimer Disease/genetics
  • Amyloid beta-Protein Precursor/genetics
  • Animals
  • Astrocytes/cytology
  • Brain/metabolism
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Homozygote
  • Humans
  • Mice
  • Mice, Transgenic
  • NF-E2-Related Factor 2/genetics
  • Neuroprotection/genetics
  • Phenotype
  • Phosphorylation
  • Proteostasis/genetics
  • Proto-Oncogene Proteins/genetics
  • Signal Transduction
  • Trans-Activators/genetics
  • tau Proteins/genetics


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