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

一种独特的基于外泌体的方法来识别阿尔茨海默病的新型生物标志物

• 批准号: 10354433
• 负责人: Gagan Deep
• 金额: $ 42.63万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10354433
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Anatomy; Archives; Astrocytes; Autopsy; Biological Markers; Biology; Biotin; Blood; Blood Circulation; Brain; Brain region; Caliber; Cells; Cerebellum; Clinical; Cognition; Cognitive; Coupled; Dementia; Development; Diagnosis; Diagnostic tests; Disease; Disease Progression; Early Diagnosis; Flow Cytometry; Freezing; GLAST Protein; Genetic Markers; Hippocampus (Brain); Individual; Knowledge; Label; Lipids; Mass Spectrum Analysis; Measures; Mediator of activation protein; Membrane Proteins; Metabolic; Metabolic Marker; Methods; Molecular; Neural Cell Adhesion Molecule L1; Neurons; Onset of illness; Outcome; Pathogenesis; Pathogenicity; Pathologic; Phase; Physiological; Plasma; Positron-Emission Tomography; Prevention; Problem Solving; Prognosis; Proteins; RNA; Role; Sampling; Site; Surface; Symptoms; Techniques; Therapeutic; base; biomarker development; brain cell; brain tissue; burden of illness; cell type; diagnostic biomarker; disease diagnosis; entorhinal cortex; exosome; experience; extracellular vesicles; innovation; liquid biopsy; mild cognitive impairment; nanoflow cytometry; noninvasive diagnosis; novel; novel marker; peripheral blood; potential biomarker; pre-clinical; protein biomarkers; specific biomarkers; tau Proteins; tau-1; tool

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.

项目摘要/摘要 阿尔茨海默氏病（AD）具有巨大的疾病负担，预计AD病例将增加约3倍 2050年。早期诊断出阿尔茨海默氏病的挑战，表明是 理想的临床需求以开发出其他非侵入性诊断测试，理想情况下是外周血。 考虑到零星的阿尔茨海默氏病在临床前具有数十年的临床前阶段 出现症状，表明阿尔茨海默氏病的生物标志物将是无价的帮助 对于预防研究和治疗方法。发现大脑衍生的外泌体 循环导致研究研究了他们作为潜在介体的作用以及“液体活检”的作用 阿尔茨海默氏病和相关痴呆症（ADRD）。这些研究很有希望，但是这些研究受到 事实证明，用于与等离子体隔离的表面标记是通用的，并且不提供任何信息 在它们起源的大脑区域上，甚至不是CNS特定的。基于我们的当前 知识，不可能从与阿尔茨海默氏病有关的血液中拉出外泌体 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更改 目前遗漏了疾病发病机理。我们的小组已经开发了独特的工具和技术 外泌体领域，这对于解决此问题可能很有用。这些创新工具可能在 鉴定独特的蛋白质仅呈现海马分泌（Exohippo）和 内嗅皮层（EXOEC），但在两个温和认知的小脑（EXOCB）分泌的外泌体中不存在 障碍（MCI）和阿尔茨海默氏病阶段。独特的表面蛋白将用于拉动exohippo 和血液中的Exoec并分析了阿尔茨海默氏病的生物标志物。以下是两个集成的 目的：I。确定海马和海马分泌的外泌体表面上存在的独特蛋白质 阿尔茨海默氏病的内嗅皮质。 ii。分离和表征海马和内嗅皮层 血浆的特定外泌体。拟议的研究具有很高的创新性，因为目前我们缺乏任何信息 关于大脑区域特异性外泌体。成功的结果将对发展小说产生重大影响， 阿尔茨海默氏病的早期和可靠的生物标志物。此外，这种方法提供了一种不太侵入性的方法 辨别阿尔茨海默氏病的分子发病机理。