Mitochondrial RNA in Alzheimer's Disease Circulating Extracellular Vesicles.
Mitochondrial RNA in Alzheimer's Disease Circulating Extracellular Vesicles.
复制标题
DOI：
10.3389/fcell.2020.581882
复制
发表时间：
2020
影响因子：
5.5
通讯作者：
Gorospe M
中科院分区：
文献类型：
--
作者：
Kim KM;Meng Q;Perez de Acha O;Mustapic M;Cheng A;Eren E;Kundu G;Piao Y;Munk R;Wood WH 3rd;De S;Noh JH;Delannoy M;Cheng L;Abdelmohsen K;Kapogiannis D;Gorospe M
阿尔茨海默病（AD）是最常见的痴呆症类型。β淀粉样蛋白（Aβ）斑块、含tau蛋白的神经元缠结和导致脑萎缩的神经元丢失是AD的病理学标志。鉴于早期诊断的重要性，已经进行了广泛的努力来鉴定AD的诊断和预后生物标志物。循环细胞外囊泡（EV）为AD的“液体活检”生物标志物提供了平台。在这里，我们描述了年龄匹配的个体的血浆EV的RNA含量，这些个体认知正常（健康对照（HC））或具有由于AD引起的轻度认知障碍（MCI）或具有轻度AD痴呆（AD）。使用RNA测序分析，我们发现，与HC相比，MCI和AD个体的血浆EV中的线粒体（mt）-RNA，包括MT-ND 1 -6 mRNA和其他蛋白质编码和非编码mt-RNA显著升高。在暴露于与AD发病机制相关的毒性条件（Aβ聚集体和H2 O2）后，培养的星形胶质细胞、小胶质细胞和神经元分泌的EV含有线粒体结构（通过电子显微镜检测）以及线粒体RNA和蛋白。我们提出，在AD脑中，毒性引起的线粒体损伤导致线粒体组分在EV中输出的包装，并进一步提出，血浆EV中的mt-RNA可以作为MCI和AD的诊断和预后生物标志物。
Alzheimer’s disease (AD) is the most common type of dementia. Amyloid β (Aβ) plaques, tau-containing neurofibrillary tangles, and neuronal loss leading to brain atrophy are pathologic hallmarks of AD. Given the importance of early diagnosis, extensive efforts have been undertaken to identify diagnostic and prognostic biomarkers for AD. Circulating extracellular vesicles (EVs) provide a platform for “liquid biopsy” biomarkers for AD. Here, we characterized the RNA contents of plasma EVs of age-matched individuals who were cognitively normal (healthy controls (HC)) or had mild cognitive impairment (MCI) due to AD or had mild AD dementia (AD). Using RNA sequencing analysis, we found that mitochondrial (mt)-RNAs, including MT-ND1-6 mRNAs and other protein-coding and non-coding mt-RNAs, were strikingly elevated in plasma EVs of MCI and AD individuals compared with HC. EVs secreted from cultured astrocytes, microglia, and neurons after exposure to toxic conditions relevant to AD pathogenesis (Aβ aggregates and H2O2), contained mitochondrial structures (detected by electron microscopy) and mitochondrial RNA and protein. We propose that in the AD brain, toxicity-causing mitochondrial damage results in the packaging of mitochondrial components for export in EVs and further propose that mt-RNAs in plasma EVs can be diagnostic and prognostic biomarkers for MCI and AD.