Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology
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Published:2022-01-10
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Jiwaji ZoebORCID, Tiwari Sachin S., Avilés-Reyes Rolando X., Hooley Monique, Hampton David, Torvell MeganORCID, Johnson Delinda A., McQueen JamieORCID, Baxter Paul, Sabari-Sankar Kayalvizhi, Qiu Jing, He Xin, Fowler Jill, Febery James, Gregory JennaORCID, Rose Jamie, Tulloch Jane, Loan JamieORCID, Story David, McDade Karina, Smith Amy M., Greer Peta, Ball Matthew, Kind Peter C., Matthews Paul M.ORCID, Smith Colin, Dando OwenORCID, Spires-Jones Tara L.ORCID, Johnson Jeffrey A.ORCID, Chandran Siddharthan, Hardingham Giles E.ORCID
Abstract
AbstractAlzheimer’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 MAPTP301S 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.
Funder
RCUK | Medical Research Council
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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