A unique exosome-based approach to identify novel biomarkers for Alzheimer's disease

项目总结/摘要 阿尔茨海默氏病（AD）具有巨大的疾病负担，并且AD病例预计到2020年将增加约3倍。 2050年。在阿尔茨海默病的早期诊断中有几个挑战，表明 开发额外的非侵入性诊断测试的显著临床需求，理想地来自外周血。 考虑到散发性阿尔茨海默病在临床治疗之前有长达数十年的临床前阶段， 症状出现时，指示阿尔茨海默病开始的生物标志物将有非常宝贵的帮助。 用于预防研究和治疗方法。脑源性外泌体的发现 循环导致研究检查它们作为潜在介质的作用以及“液体活组织检查”， 阿尔茨海默病和相关痴呆症（ADRD）。这些研究是有希望的，但这些都受到限制， 用于从血浆中分离的表面标记物是通用的，不提供任何信息 在它们起源的大脑区域，甚至不是中枢神经系统特异性的。根据我们目前的 知识，不可能从与阿尔茨海默病相关的大脑有关的血液中取出外泌体 区域（例如，海马和内嗅皮层）;因此，与阿尔茨海默氏症相关的特定变化 疾病的发病机制目前被忽略。我们的团队开发了独特的工具和技术， 外泌体领域，这可能是有用的，在解决这个问题。这些创新的工具可能有助于 鉴定仅存在于海马分泌的外来体表面的独特蛋白质（ExoHippo）， 内嗅皮层（ExoEC），但在小脑分泌的外泌体（ExoCB）中缺失， 损害（MCI）和阿尔茨海默病阶段。独特的表面蛋白质将被用来拉出ExoHippo 和ExoEC，并分析阿尔茨海默病的生物标志物。以下是两个综合 目的：I.为了鉴定海马分泌的外泌体表面上存在的独特蛋白质， 内嗅皮层在阿尔茨海默病中的作用二.分离并鉴定海马体和内嗅皮层- 从血浆中提取特定的外泌体。拟议的研究具有高度创新性，因为目前我们缺乏任何信息， 关于大脑区域特异性外泌体。成功的结果将对开发新的， 早期和可靠的阿尔茨海默病生物标志物。此外，这种方法提供了一种侵入性较小的方法， 了解阿尔茨海默病的分子发病机制。

Project Summary/Abstract Alzheimer's disease (AD) has a huge disease burden, and AD cases are expected to increase by ~3-fold by the year 2050. There are several challenges in the early diagnosis of Alzheimer's disease, indicating a significant clinical need to develop additional non-invasive diagnostic tests, ideally from peripheral blood. Considering that sporadic Alzheimer's disease has a preclinical phase of up to decades before clinical symptoms arise, biomarker/s that would indicate the start of Alzheimer's disease would be of invaluable help for both prevention studies and therapeutic approaches. The discovery of brain-derived exosomes in the circulation has led to studies examining their role as potential mediators as well as `liquid biopsies' for Alzheimer's disease and related dementias (ADRD). These studies are promising, but these are limited by the fact that surface markers used for their isolation from plasma are generic and do not provide any information on the brain region from which they originate, and are not even CNS specific. Based upon our current knowledge, it is not possible to pullout exosomes from blood pertaining to Alzheimer's disease-relevant brain regions (e.g., hippocampus and entorhinal cortex); therefore, specific changes associated with Alzheimer's disease pathogenesis are currently missed. Our group has developed unique tools and techniques in the exosome field, which could be useful in solving this problem. These innovative tools could be useful in identifying unique proteins present only the surface of exosomes secreted by the hippocampus (ExoHippo) and entorhinal cortex (ExoEC) but absent in exosomes secreted by the cerebellum (ExoCB) at both mild-cognitive impairment (MCI) and Alzheimer's disease stages. The unique surface proteins will be used to pullout ExoHippo and ExoEC from blood and analyze for biomarkers of Alzheimer's disease. Following are the two integrated aims: I. To identify unique proteins present on the surface of exosomes secreted by hippocampus and entorhinal cortex in Alzheimer's disease. II. To isolate and characterize hippocampus- and entorhinal cortex- specific exosomes from plasma. Proposed studies are highly innovative, as currently, we lack any information about brain region-specific exosomes. Successful outcomes will have a significant impact in developing novel, early and reliable biomarkers for Alzheimer's disease. Further, this approach offers a less invasive way to discern the molecular pathogenesis of Alzheimer's disease.