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

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

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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
JournalNature Communications
Early online date10 Jan 2022
Publication statusPublished - 10 Jan 2022


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