Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology.
Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology.
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DOI：
10.1038/s41467-021-27702-w
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发表时间：
2022-01-10
影响因子：
16.6
通讯作者：
Hardingham GE
中科院分区：
文献类型：
--
作者：
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
阿尔茨海默氏病（AD）改变星形胶质细胞，但对Akt和Tau病理学的影响知之甚少。APP/PS1 β-淀粉样蛋白病和MAPTP 301 S tau蛋白病小鼠中星形胶质细胞的TRAP-seq翻译组分析显示，只有Ablad 3影响AD风险基因的表达，但两种病理都过早诱导了年龄依赖性变化，并且在人类死后AD星形胶质细胞中发现了不同但重叠的特征。Akt和Tau病理学均诱导星形胶质细胞签名，涉及生物能量和翻译机制的抑制，以及炎症途径加上蛋白质降解/蛋白质稳态基因的诱导，后者富含炎症介质Spi 1和应激激活的细胞保护性Nrf 2的靶点。星形胶质细胞特异性Nrf 2表达诱导了反应性表型，其重现了这种蛋白质稳态特征的要素，减少了各自模型中的ARF沉积和磷酸化tau积累，并挽救了全脑转录失调、细胞病理学、神经变性和行为/认知缺陷。因此，Akt和Tau诱导与有害和适应性保护信号相关的重叠星形胶质细胞谱，后者可以减缓病理进展。阿尔茨海默病与星形胶质细胞的变化有关。在这里，作者研究了与淀粉样蛋白和tau病理学相关的星形胶质细胞翻译组。
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 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. Alzheimer’s disease is associated with changes in astrocytes. Here the authors investigated the astrocyte translatome associated with amyloid-ß and tau pathology.
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影响因子：
6.1
作者：
Cunningham, C;Deacon, RMJ;Perry, VH
通讯作者：
Perry, VH
DOI：
10.4049/jimmunol.1600043
发表时间：
2016-10-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gomez JC;Dang H;Martin JR;Doerschuk CM
通讯作者：
Doerschuk CM
影响因子：
16.2
作者：
Burda JE;Sofroniew MV
通讯作者：
Sofroniew MV
影响因子：
9.3
作者：
Das, Sudeshna;Li, Zhaozhi;Serrano-Pozo, Alberto
通讯作者：
Serrano-Pozo, Alberto
影响因子：
9.3
作者：
Carter, Stephen F.;Scholl, Michael;Nordberg, Agneta
通讯作者：
Nordberg, Agneta