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 - Aviles-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 A.
AU - Gregory, Jenna M
AU - Rose, Jamie
AU - Tulloch, Jane
AU - Loan, James
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
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.).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/1/10
Y1 - 2022/1/10
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-021-27702-w
DO - 10.1038/s41467-021-27702-w
M3 - Article
C2 - 35013236
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
M1 - 135
ER -