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，其特征在于 进行性认知障碍，包括记忆丧失。疾病的机制 进展尚未完全阐明，迄今为止，没有可靠的生物标志物， 检测致病成分。提高评估中枢神经系统的能力 使用外周生物流体样本（液体活检）进行大脑健康将扩大临床选择 疾病的阶段。 脑源性细胞外囊泡（EV）（bdEV）穿过生物屏障， 回到特定的亲本细胞类型，提出新的诊断、预后和监测工具， 革命性的识别和护理AD以及了解发病机制。bdEV 携带参与神经传递或神经保护的货物并促进交流 也使它们成为病理学的“靶向因子”。 为了为更有效的外周bdEV研究奠定基础，我们比较了 对照和晚期AD脑的具有纯化EV级分的脑匀浆的含量。 蛋白质组差异在EV中最为明显，而某些细胞释放更多EV或 具有更高密度的细胞特异性表面标志物的EV。基于这些新发现，我们 建议使用神经元、星形胶质细胞和神经胶质细胞的人诱导多能干细胞（hiPSC）模型， 小胶质细胞，以测试我们确定的顶级CNS表面标志物的特异性和敏感性， 我们的初步研究富集了来自不同细胞类型的bdEV， 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 蛋白质和RNA的差异调节AD bdEV，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用于疾病检测的新分子特征 和监测。

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.