Multi-Omics Analysis of Microglial Extracellular Vesicles From Human Alzheimer's Disease Brain Tissue Reveals Disease-Associated Signatures.
Multi-Omics Analysis of Microglial Extracellular Vesicles From Human Alzheimer's Disease Brain Tissue Reveals Disease-Associated Signatures.
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DOI：
10.3389/fphar.2021.766082
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发表时间：
2021
影响因子：
5.6
通讯作者：
Bilousova T
中科院分区：
文献类型：
--
作者：
Cohn W;Melnik M;Huang C;Teter B;Chandra S;Zhu C;McIntire LB;John V;Gylys KH;Bilousova T
阿尔茨海默病（AD）是痴呆症最常见的病因，但在出现临床症状之前没有治愈或诊断方法。细胞外囊泡（EVs）是一种由脂质双层分隔的颗粒，几乎可以从所有类型的细胞中释放出来。全基因组关联研究已将多种阿尔茨海默病遗传风险因素与小胶质细胞特异性途径联系起来。小胶质细胞衍生的EVs可能通过促进不溶性致病性蛋白（如tau和a β）的传播而在AD的进展中发挥作用，这是合理的。尽管电动汽车作为诊断工具的潜在效用，我们对人脑电动汽车亚群的了解是有限的。在这里，我们提出了一种从冷冻保存的人脑组织中分离小胶质细胞cd11b阳性小ev的方法，以及从4例晚期AD （Braak V-VI）和3例年龄匹配的正常/低病理（NL）病例的顶叶皮层富集的小胶质ev的综合多组学分析。该综合分析分别使用散弹枪蛋白质组学、靶向脂质组学和NanoString nCounter技术揭示了1000种蛋白质、594种脂质和105种mirna。结果显示，与NL病例相比，AD脑cd11b阳性ev中稳态小胶质细胞标志物P2RY12和TMEM119的丰度显著降低，疾病相关小胶质细胞标志物FTH1和TREM2的水平升高。Tau丰度在AD脑源性小胶质EVs中显著升高。这些变化伴随着AD组突触和神经元特异性蛋白的上调。阿尔茨海默病大脑的小胶质细胞EVs中游离胆固醇水平升高。脂质组学分析还揭示了促炎脂质谱、内溶酶体功能障碍以及与ad相关的含有二十二碳六烯酸（DHA）的多不饱和脂质水平显著下降，表明酰基链重构存在潜在缺陷。此外，与免疫和细胞衰老信号通路相关的四种mirna在AD组中显著上调。我们的数据表明，AD晚期稳态小胶质细胞特征的丧失可能伴随着内溶酶体损伤以及未消化的神经元和髓鞘碎片（包括tau）通过细胞外囊泡释放。我们认为，对小胶质细胞来源的ev的分析具有识别新的ev相关生物标志物的优点，并为未来对患者来源的细胞类型特异性ev的更大规模多组学研究提供框架。
Alzheimer’s disease (AD) is the most common cause of dementia, yet there is no cure or diagnostics available prior to the onset of clinical symptoms. Extracellular vesicles (EVs) are lipid bilayer-delimited particles that are released from almost all types of cell. Genome-wide association studies have linked multiple AD genetic risk factors to microglia-specific pathways. It is plausible that microglia-derived EVs may play a role in the progression of AD by contributing to the dissemination of insoluble pathogenic proteins, such as tau and Aβ. Despite the potential utility of EVs as a diagnostic tool, our knowledge of human brain EV subpopulations is limited. Here we present a method for isolating microglial CD11b-positive small EVs from cryopreserved human brain tissue, as well as an integrated multiomics analysis of microglial EVs enriched from the parietal cortex of four late-stage AD (Braak V-VI) and three age-matched normal/low pathology (NL) cases. This integrated analysis revealed 1,000 proteins, 594 lipids, and 105 miRNAs using shotgun proteomics, targeted lipidomics, and NanoString nCounter technology, respectively. The results showed a significant reduction in the abundance of homeostatic microglia markers P2RY12 and TMEM119, and increased levels of disease-associated microglia markers FTH1 and TREM2, in CD11b-positive EVs from AD brain compared to NL cases. Tau abundance was significantly higher in AD brain-derived microglial EVs. These changes were accompanied by the upregulation of synaptic and neuron-specific proteins in the AD group. Levels of free cholesterol were elevated in microglial EVs from the AD brain. Lipidomic analysis also revealed a proinflammatory lipid profile, endolysosomal dysfunction, and a significant AD-associated decrease in levels of docosahexaenoic acid (DHA)-containing polyunsaturated lipids, suggesting a potential defect in acyl-chain remodeling. Additionally, four miRNAs associated with immune and cellular senescence signaling pathways were significantly upregulated in the AD group. Our data suggest that loss of the homeostatic microglia signature in late AD stages may be accompanied by endolysosomal impairment and the release of undigested neuronal and myelin debris, including tau, through extracellular vesicles. We suggest that the analysis of microglia-derived EVs has merit for identifying novel EV-associated biomarkers and providing a framework for future larger-scale multiomics studies on patient-derived cell-type-specific EVs.
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影响因子：
4.2
作者：
Dinkins MB;Dasgupta S;Wang G;Zhu G;Bieberich E
通讯作者：
Bieberich E
影响因子：
4.8
作者：
Chan, Robin B.;Oliveira, Tiago G.;Di Paolo, Gilbert
通讯作者：
Di Paolo, Gilbert
影响因子：
15.1
作者：
Clayton K;Delpech JC;Herron S;Iwahara N;Ericsson M;Saito T;Saido TC;Ikezu S;Ikezu T
通讯作者：
Ikezu T
影响因子：
4.8
作者：
Brioschi S;d'Errico P;Amann LS;Janova H;Wojcik SM;Meyer-Luehmann M;Rajendran L;Wieghofer P;Paolicelli RC;Biber K
通讯作者：
Biber K
DOI：
10.18632/aging.101203
发表时间：
2017-03-23
期刊：
Aging
影响因子：
--
作者：
Abdullah L;Evans JE;Emmerich T;Crynen G;Shackleton B;Keegan AP;Luis C;Tai L;LaDu MJ;Mullan M;Crawford F;Bachmeier C
通讯作者：
Bachmeier C