Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer's disease.
Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer's disease.
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DOI：
10.1186/s13024-018-0254-8
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发表时间：
2018-05-21
影响因子：
15.1
通讯作者：
Levey AI
中科院分区：
文献类型：
--
作者：
Rangaraju S;Dammer EB;Raza SA;Rathakrishnan P;Xiao H;Gao T;Duong DM;Pennington MW;Lah JJ;Seyfried NT;Levey AI
疾病相关小胶质细胞 (DAM) 代表转录上不同的和神经退行性疾病特异性的小胶质细胞特征，在阿尔茨海默病 (AD) 中的意义尚不清楚。了解 DAM 及其关键调节因子的异质性可以指导临床前实验和药物发现。将加权共表达网络分析（WGCNA）应用于来自神经炎症和神经退行性疾病小鼠模型的现有小胶质细胞转录组数据集，以识别高度共表达基因的模块。这些模块与稳态小胶质细胞和 DAM 的已知特征进行对比，揭示了 DAM 内新的分子异质性。进行流式细胞术验证研究以确认 WGCNA 预测的 AD 小鼠模型中存在不同的 DAM 亚群。基因本体分析与生物信息学方法相结合揭示了小胶质细胞模块的药物靶点和转录调节因子，预计可以有利地调节 AD 中的神经炎症。这些指导了神经炎症和神经变性（5xFAD）小鼠模型的体内和体外研究，以确定抑制促炎基因表达和促进淀粉样蛋白清除是否可行。我们通过将我们的结果与 AD 全基因组关联研究以及人类 AD 和非疾病死后大脑蛋白质组相结合，确定了这些发现的人类相关性。将 WGCNA 应用于小胶质细胞基因表达数据揭示了小胶质细胞激活的转录组框架，该框架预测了 DAM 内不同的促炎和抗炎表型，我们通过流式细胞术在 AD 和衰老模型中证实了这一点。促炎性 DAM 在 AD 小鼠模型中较早出现，其特征是促炎基因（Tlr2、Ptgs2、Il12b、Il1b）、表面标记 CD44、钾通道 Kv1.3 和调节因子（NFkb、Stat1、RelA），而抗炎 DAM 表达吞噬基因（Igf1、Apoe、Myo1e）、具有不同调节因子的表面标记 CXCR4（LXRα/β、 ATF1）。作为神经免疫调节策略，我们验证了 ShK-223 肽的 LXRα/β 激动和 Kv1.3 阻断作用，可促进抗炎 DAM、抑制促炎 DAM 并增强 AD 模型中的 Aβ 清除率。人类 AD 风险基因在稳态小胶质细胞中高度表达，表明 AD 早期小胶质细胞失调的因果作用。促炎性 DAM 蛋白与神经病理学呈正相关，并且先于认知能力下降，这证实了抑制促炎性 DAM 在 AD 中的治疗意义。我们提供了神经退行性变中小胶质细胞激活的预测转录组框架，可以指导临床前研究来表征和治疗调节 AD 中的神经炎症。本文的在线版本 (10.1186/s13024-018-0254-8) 包含补充材料，可供授权用户使用。
Disease-associated-microglia (DAM) represent transcriptionally-distinct and neurodegeneration-specific microglial profiles with unclear significance in Alzheimer’s disease (AD). An understanding of heterogeneity within DAM and their key regulators may guide pre-clinical experimentation and drug discovery. Weighted co-expression network analysis (WGCNA) was applied to existing microglial transcriptomic datasets from neuroinflammatory and neurodegenerative disease mouse models to identify modules of highly co-expressed genes. These modules were contrasted with known signatures of homeostatic microglia and DAM to reveal novel molecular heterogeneity within DAM. Flow cytometric validation studies were performed to confirm existence of distinct DAM sub-populations in AD mouse models predicted by WGCNA. Gene ontology analyses coupled with bioinformatics approaches revealed drug targets and transcriptional regulators of microglial modules predicted to favorably modulate neuroinflammation in AD. These guided in-vivo and in-vitro studies in mouse models of neuroinflammation and neurodegeneration (5xFAD) to determine whether inhibition of pro-inflammatory gene expression and promotion of amyloid clearance was feasible. We determined the human relevance of these findings by integrating our results with AD genome-wide association studies and human AD and non-disease post-mortem brain proteomes. WGCNA applied to microglial gene expression data revealed a transcriptomic framework of microglial activation that predicted distinct pro-inflammatory and anti-inflammatory phenotypes within DAM, which we confirmed in AD and aging models by flow cytometry. Pro-inflammatory DAM emerged earlier in mouse models of AD and were characterized by pro-inflammatory genes (Tlr2, Ptgs2, Il12b, Il1b), surface marker CD44, potassium channel Kv1.3 and regulators (NFkb, Stat1, RelA) while anti-inflammatory DAM expressed phagocytic genes (Igf1, Apoe, Myo1e), surface marker CXCR4 with distinct regulators (LXRα/β, Atf1). As neuro-immunomodulatory strategies, we validated LXRα/β agonism and Kv1.3 blockade by ShK-223 peptide that promoted anti-inflammatory DAM, inhibited pro-inflammatory DAM and augmented Aβ clearance in AD models. Human AD-risk genes were highly represented within homeostatic microglia suggesting causal roles for early microglial dysregulation in AD. Pro-inflammatory DAM proteins were positively associated with neuropathology and preceded cognitive decline confirming the therapeutic relevance of inhibiting pro-inflammatory DAM in AD. We provide a predictive transcriptomic framework of microglial activation in neurodegeneration that can guide pre-clinical studies to characterize and therapeutically modulate neuroinflammation in AD. The online version of this article (10.1186/s13024-018-0254-8) contains supplementary material, which is available to authorized users.
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影响因子：
5.3
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph
影响因子：
7.1
作者：
Holtman IR;Raj DD;Miller JA;Schaafsma W;Yin Z;Brouwer N;Wes PD;Möller T;Orre M;Kamphuis W;Hol EM;Boddeke EW;Eggen BJ
通讯作者：
Eggen BJ
影响因子：
16.6
作者：
Chiang EY;Li T;Jeet S;Peng I;Zhang J;Lee WP;DeVoss J;Caplazi P;Chen J;Warming S;Hackos DH;Mukund S;Koth CM;Grogan JL
通讯作者：
Grogan JL
DOI：
10.1084/jem.20142322
发表时间：
2015-03-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jay TR;Miller CM;Cheng PJ;Graham LC;Bemiller S;Broihier ML;Xu G;Margevicius D;Karlo JC;Sousa GL;Cotleur AC;Butovsky O;Bekris L;Staugaitis SM;Leverenz JB;Pimplikar SW;Landreth GE;Howell GR;Ransohoff RM;Lamb BT
通讯作者：
Lamb BT
影响因子：
14.8
作者：
Korin, Ben;Dubovik, Tania;Rolls, Asya
通讯作者：
Rolls, Asya