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

被引：116

作者：

Jiwaji, Zoeb ^{[1
,2
]}

Tiwari, Sachin S. ^{[1
,3
]}

Aviles-Reyes, Rolando X. ^{[4
]}

Hooley, Monique ^{[1
,3
]}

Hampton, David ^{[1
,3
]}

Torvell, Megan ^{[1
,3
,5
]}

Johnson, Delinda A. ^{[4
]}

McQueen, Jamie ^{[1
,2
]}

Baxter, Paul ^{[1
,2
]}

Sabari-Sankar, Kayalvizhi ^{[4
]}

Qiu, Jing ^{[1
,2
]}

He, Xin ^{[1
,2
]}

Fowler, Jill ^{[2
]}

Febery, James ^{[2
]}

Gregory, Jenna ^{[1
,3
]}

Rose, Jamie ^{[1
,2
]}

Tulloch, Jane ^{[1
,2
]}

Loan, Jamie ^{[1
,2
]}

Story, David ^{[1
,3
]}

McDade, Karina ^{[1
]}

Smith, Amy M. ^{[6
]}

Greer, Peta ^{[1
,2
]}

Ball, Matthew ^{[1
,2
]}

Kind, Peter C. ^{[1
,7
]}

Matthews, Paul M. ^{[6
]}

Smith, Colin ^{[3
]}

Dando, Owen ^{[1
,2
,7
]}

Spires-Jones, Tara L. ^{[1
,2
]}

Johnson, Jeffrey A. ^{[4
]}

Chandran, Siddharthan ^{[1
,3
]}

Hardingham, Giles E. ^{[1
,2
]}

机构：

[1] Univ Edinburgh, UK Dementia Res Inst, Edinburgh Med Sch, Chancellors Bldg, Edinburgh EH16 4SB, Midlothian, Scotland

[2] Univ Edinburgh, Ctr Discovery Brain Sci, Hugh Robson Bldg,George Sq, Edinburgh EH8 9XD, Midlothian, Scotland

[3] Univ Edinburgh, Ctr Clin Brain Sci, Chancellors Bldg, Edinburgh, Midlothian, Scotland

[4] Univ Wisconsin, Sch Pharm, Div Pharmaceut Sci, 425 N Charter St, Madison, WI 53706 USA

[5] Cardiff Univ, UK Dementia Res Inst, Hadyn Ellis Bldg, Cardiff CF24 4HQ, Wales

[6] Imperial Coll, Hammersmith Hosp, UK Dementia Res Inst, Burlington Danes Bldg, London W12 0NN, England

[7] Univ Edinburgh, Simons Initiat Developing Brain, Hugh Robson Bldg,George Sq, Edinburgh EH8 9XD, Midlothian, Scotland

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

基金：

欧洲研究理事会; 英国医学研究理事会;

关键词：

TRANSCRIPTION FACTOR NRF2; ALZHEIMERS-DISEASE; AMYLOID-BETA; MOUSE MODEL; EXPRESSION; PROTECTS; CNS; NEURODEGENERATION; DYSFUNCTION; INDIVIDUALS;

D O I：

10.1038/s41467-021-27702-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Alzheimer's disease (AD) alters astrocytes, but the effect of A beta and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 beta-amyloidopathy and MAPT(P301S) tauopathy mice revealed that only A beta 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 beta 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 beta deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, A beta and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.

引用

页数：23