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.
| Original language | English |
|---|---|
| Article number | 135 |
| Number of pages | 23 |
| Journal | Nature Communications |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 10 Jan 2022 |
Bibliographical note
Funding Information:We thank Michel Goedert for the MAPTP301S mouse and Nathaniel Heintz for the Aldh1l1_eGFP-RPL10a mouse. This work was funded by the UK Dementia Research Institute (G.E.H., S.C.) which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK, the European Research Council (ERC) under the EU’s Horizon 2020 research and innovation programme (Grant No. 681181, T.S.J.) and grant NIH P50 AG033514 (Project 1, J.A.J.).
Data Availability Statement
RNA-seq data is generated in this study available from the European Nucleotide Archive (accession number: E-MTAB-10985, https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-10985). Source data are provided with this paper.Code Availability
The Python tool to disambiguate mixed-species high-throughput sequencing reads according to species is available at https://github.com/biomedicalinformaticsgroup/Sargasso.
Keywords
- 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
Access to Document
- Jiwaji_etal_NC_Reactive_Astrocytes_Acquire_VOR
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