Alzheimer's disease-specific extracellular vesicles: from pathology to novel biomarker discovery

摘要 阿尔茨海默病(AD)是最具破坏性的神经系统疾病之一，其特征是 进行性认知障碍，包括记忆力丧失。疾病的发病机制 进展尚未完全阐明，到目前为止，还没有可靠的生物标志物来预测早期 致病成分的检测。提高了评估中枢神经系统的能力 外周生物体液样本(液体活检)的脑健康将完全扩大临床选择 疾病的各个阶段。 脑源性细胞外小泡(BdEvs)跨越生物屏障，可追溯 回到特定的亲代细胞类型，建议新的诊断、预后和监测工具， 革命性地对AD的识别和护理以及对发病机制的理解。BdEV 携带涉及神经传递或神经保护的货物，促进沟通 脑细胞之间的相互作用也使它们成为病理的“靶标”。 为了为更有效的外周BDEV研究奠定基础，我们比较了这些蛋白质 对照组和晚期阿尔茨海默病患者脑匀浆与纯化的EV组分的含量。 蛋白质组的差异在EVS中最为明显，而某些细胞释放更多EVS或 细胞特异性表面标记密度较高的EVS。基于这些新发现，我们 建议使用人类诱导多能干细胞(HiPSC)模型建立神经元、星形胶质细胞和 小胶质细胞来测试我们在 我们的初步研究丰富了来自不同细胞类型的bdEv，并在 AD患者与对照组(目标1)。研究与衰老和神经退行性变相关的 在AD bdEV中差异调控的蛋白质和RNA，我们将研究三个不同的 EV的来源，包括IPSC衍生的后代(AIM 1)、脑组织(AIM 2)和血浆(AIM 3)。我们将使用相同的来源来发现新的用于疾病检测的分子特征 并进行监控。

ABSTRACT Alzheimer’s disease (AD) is one of the most devastating neurological diseases characterized by progressive cognitive impairments, including memory loss. The mechanisms of disease progression are not yet fully elucidated, and to date there are no reliable biomarkers for early detection of pathogenic components. Improved capabilities to assess central nervous system brain health with peripheral biofluid samples (Liquid Biopsy) will expand clinical options at all stages of disease. Extracellular vesicles (EVs) of brain origin (bdEVs) cross biological barriers and can be traced back to specific parent cell types suggesting novel diagnostic, prognostic, and monitoring tools, revolutionizing identification and care of AD as well as understanding pathogenesis. bdEVs carry cargos involved in neurotransmission or neuroprotection and facilitate communication between brain cells also making them “targetable agents” of pathology. To lay the groundwork for more efficient peripheral bdEV studies, we have compared the protein content of brain homogenates with purified EV fractions of control and late-stage AD brains. Proteome differences were most pronounced in EVs, while certain cells release more EVs or EVs with higher density of cell-specific surface markers. Based on these novel findings, we propose to use human induced pluripotent stem cell (hiPSC) models of neurons, astrocytes and microglia to test the specificity and sensitivity of the top CNS surface markers we identified in our preliminary studies as enriched on bdEVs from different cell types and as more abundant in AD patients versus controls (Aim 1). To investigate aging- and neurodegeneration-related proteins and RNAs that were differentially regulated in AD bdEVs, we will study three different sources of EVs, including iPSC-derived progeny (Aim 1), brain tissue (Aim 2), and plasma (Aim 3). We will use the same sources to discover new molecular signatures for disease detection and monitoring.