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

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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