ALZHEIMER'S DISEASE BEFORE PLAQUES AND TANGLES: Abeta-AMYLOID OLIGOMERS AND THE GLYMPHATIC PATHWAY

出现斑块和缠结之前的阿尔茨海默病：Aβ-淀粉样蛋白寡聚物和类淋巴通路

• 批准号: 9297553
• 负责人: JUAN TRONCOSO
• 金额: $ 20.44万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9297553
• 关键词: Abeta clearance; Age; Age-Years; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Apolipoprotein E; Astrocytes; Autopsy; Biological Markers; Blood - brain barrier anatomy; Brain; Cell model; Cerebrospinal Fluid; Cervical; Cervical lymph node group; Collection; Confocal Microscopy; Cultured Cells; Development; Future; Genotype; Goals; Human; Impairment; Individual; Lesion; Lymphatic; Mus; Nature; Neuraxis; Neurofibrillary Tangles; Observational Study; Pathologic; Pathway interactions; Pattern; Physiologic pulse; Preventive Intervention; Process; Public Health; Role; Specimen; System; Tauopathies; Testing; Time; Tissue Model; Tissues; Western Blotting; abeta accumulation; abeta deposition; abeta oligomer; aquaporin 4; base; cerebrospinal fluid flow; cerebrovascular; extracellular; glymphatic system; human subject; immunocytochemistry; novel; protein metabolite; tau Proteins; wasting; water channel

PROJECT SUMMARY There is substantial evidence that soluble Aβ oligomers are neurotoxic1-5 and that impaired clearance of soluble Aβ is a critical pathologic mechanism in late-onset AD, a concept supported by the observation of decreased passage of Aβ into the cerebrospinal fluid (CSF) in AD6 and the decreased levels of Aβ in the CSF of AD patients7,8,9,10. The mechanisms for clearance of extracellular Aβ from the brain are multiple11 and include local enzymatic degradation12, transport across the blood brain barrier (BBB)13-16, or via the CSF17. The relative contributions of these various systems to Aβ clearance are not fully understood, although the BBB system appears to be predominant. However, recently, the glymphatic system has been implicated in this process, possibly in addition to BBB mechanism15,16. The glymphatic system18,19 is proposed as a brain waste clearance pathway consisting of perivascular tunnels lined by astrocytes that drain into CSF and eventually into cervical lymphatic nodes20-22. This system allows for the elimination of soluble proteins and metabolites from the central nervous system and it may be implicated in Aβ clearance and the development of AD11. The clearance efficiency of the glymphatic system depends on CSF flow, cerebrovascular pulsation, and the aquaporin-4 (AQP4) water channels of perivascular astrocytes23. In mice, the efficiency of the glymphatic pathway appears compromised in aging due to impairment of AQP4 dependent bulk flow23. The role of the glymphatic system in the clearance of Aβ and its relevance to AD is based mostly on studies in rodents24,23,25, which is one of the reasons why it remains controversial26. Therefore, the relevance of the glymphatic system to AD needs to be examined in the human brain, which is the overall goal of this proposal. Moreover, we believe that the best time to conduct this examination is before and during the early stages of Aβ deposition. To this end, we have available a large number of human postmortem brains from individuals 30 to 65 years of age which are fully characterized for AD lesions and tissue integrity, and genotyped for ApoE. The exploratory and observational studies proposed here are the basis for future mechanistic examination of the glymphatic system and its relevance to AD to be conducted in cultured cells and tissues, and animal models.

项目摘要 有大量证据表明固体Aβ低聚物是神经毒素1-5，并且受损 固体Aβ的清除是晚期AD的关键病理机制，这是一个概念 在观察Aβ通过降低到脑脊液（CSF）中的支持支持 AD6和Aβ患者的Aβ水平的扩大7,8,9,10。机制 从大脑的细胞外Aβ清除为多重11，包括局部酶促 降解12，跨血脑屏障（BBB）13-16或通过CSF17的运输。亲戚 这些各种系统对Aβ清除率的贡献尚不完全了解，尽管 BBB系统似乎是主要的。但是，最近，糖基系统已经 在此过程中实施，除了BBB机制15,16之外。糖 System18,19被认为是由血管周期隧道组成的脑废清除途径 由星形胶质细胞衬里，这些星形胶质细胞排入CSF并最终进入宫颈淋巴结20-22。这 系统允许从中枢神经中消除固体蛋白质和代谢物 系统及其可能在Aβ清除率和AD11的发展中暗示。间隙 糖基系统的效率取决于CSF的流动，脑血管脉动和 血管周围星形胶质细胞的水通道23。在小鼠中， 由于AQP4依赖性体积的损害，胶状途径在衰老中似乎受到损害 Flow23。糖系统在清除Aβ及其与AD相关性中的作用是 主要基于啮齿动物的研究24,23,25，这是其仍然存在的原因之一 有争议26。因此，需要检查聚糖系统与广告的相关性 在人脑中，这是该提议的总体目标。而且，我们相信最好的 进行此检查的时间是在Aβ沉积的早期阶段和期间。对此 结局，我们有大量的人类邮政大脑30至65 年龄是针对广告病变和组织完整性充分表征的，并为基因分型 apoe。这里提出的探索性和观察性研究是未来的基础 糖系统的机械检查及其与AD的相关性 培养的细胞和组织以及动物模型。