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 McDade; Amy M. Smith; Peta Greer; Matthew Ball; Peter C. Kind; Paul M. Matthews; Colin Smith; Owen Dando; Tara L. Spires-Jones; Jeffrey A. Johnson; Siddharthan Chandran; Giles E. Hardingham

doi:10.1038/s41467-021-27702-w

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

Medical Sciences

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

Abstract

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	https://doi.org/10.1038/s41467-021-27702-w
Publication status	Published - 10 Jan 2022

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-021-27702-w

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Jiwaji, Z., Tiwari, S. S., Avilés-Reyes, R. X., Hooley, M., Hampton, D., Torvell, M., Johnson, D. A., McQueen, J., Baxter, P., Sabari-Sankar, K., Qiu, J., He, X., Fowler, J., Febery, J., Gregory, J., Rose, J., Tulloch, J., Loan, J., Story, D., ... Hardingham, G. E. (2022). Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology. Nature Communications, 13(1), [135]. https://doi.org/10.1038/s41467-021-27702-w

Jiwaji, Z, Tiwari, SS, Avilés-Reyes, RX, Hooley, M, Hampton, D, Torvell, M, Johnson, DA, McQueen, J, Baxter, P, Sabari-Sankar, K, Qiu, J, He, X, Fowler, J, Febery, J, Gregory, J, Rose, J, Tulloch, J, Loan, J, Story, D, McDade, K, Smith, AM, Greer, P, Ball, M, Kind, PC, Matthews, PM, Smith, C, Dando, O, Spires-Jones, TL, Johnson, JA, Chandran, S & Hardingham, GE 2022, 'Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology', Nature Communications, vol. 13, no. 1, 135. https://doi.org/10.1038/s41467-021-27702-w

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title = "Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and A{\ss} pathology",

abstract = "AbstractAlzheimer{\textquoteright}s disease (AD) alters astrocytes, but the effect of A{\ss} 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 A{\ss} 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 A{\ss} 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 A{\ss} deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, A{\ss} and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.",

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",

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

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{\textquoteright}s Society, and Alzheimer{\textquoteright}s Research UK, the European Research Council (ERC) under the EU{\textquoteright}s Horizon 2020 research and innovation programme (Grant No. 681181, T.S.J.) and grant NIH P50 AG033514 (Project 1, J.A.J.). ",

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month = jan,

day = "10",

doi = "10.1038/s41467-021-27702-w",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

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TY - JOUR

T1 - Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology

AU - Jiwaji, Zoeb

AU - Tiwari, Sachin S.

AU - Avilés-Reyes, Rolando X.

AU - Hooley, Monique

AU - Hampton, David

AU - Torvell, Megan

AU - Johnson, Delinda A.

AU - McQueen, Jamie

AU - Baxter, Paul

AU - Sabari-Sankar, Kayalvizhi

AU - Qiu, Jing

AU - He, Xin

AU - Fowler, Jill

AU - Febery, James

AU - Gregory, Jenna

AU - Rose, Jamie

AU - Tulloch, Jane

AU - Loan, Jamie

AU - Story, David

AU - McDade, Karina

AU - Smith, Amy M.

AU - Greer, Peta

AU - Ball, Matthew

AU - Kind, Peter C.

AU - Matthews, Paul M.

AU - Smith, Colin

AU - Dando, Owen

AU - Spires-Jones, Tara L.

AU - Johnson, Jeffrey A.

AU - Chandran, Siddharthan

AU - Hardingham, Giles E.

N1 - 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.).

PY - 2022/1/10

Y1 - 2022/1/10

N2 - 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 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.

AB - 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 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.

KW - Alzheimer Disease/genetics

KW - Amyloid beta-Protein Precursor/genetics

KW - Animals

KW - Astrocytes/cytology

KW - Brain/metabolism

KW - Disease Models, Animal

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - Homozygote

KW - Humans

KW - Mice

KW - Mice, Transgenic

KW - NF-E2-Related Factor 2/genetics

KW - Neuroprotection/genetics

KW - Phenotype

KW - Phosphorylation

KW - Proteostasis/genetics

KW - Proto-Oncogene Proteins/genetics

KW - Signal Transduction

KW - Trans-Activators/genetics

KW - tau Proteins/genetics

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UR - https://www.mendeley.com/catalogue/e7bc2cd7-6b2e-36ed-8351-e9b5c7a2cf52/

U2 - 10.1038/s41467-021-27702-w

DO - 10.1038/s41467-021-27702-w

M3 - Article

C2 - 35013236

VL - 13

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 135

ER -

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

Abstract

Keywords

UN SDGs

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