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.

项目概要 有大量证据表明可溶性 Aβ 寡聚体具有神经毒性 1-5 并且会损害 可溶性 Aβ 的清除是迟发性 AD 的一个关键病理机制，这是一个概念 Aβ 进入脑脊液 (CSF) 的通道减少的观察结果支持了这一点 AD6 和 AD 患者脑脊液中 Aβ 水平下降的机制7,8,9,10。 细胞外 Aβ 从大脑中的清除是多重的11，包括局部酶促清除 降解12，穿过血脑屏障（BBB）13-16 或通过CSF17 运输。 这些不同系统对 Aβ 清除的贡献尚未完全了解，尽管 BBB 系统似乎占主导地位，但最近，类淋巴系统已占主导地位。 参与这一过程的可能还有 BBB 机制15,16。 系统18,19被提议作为由血管周围隧道组成的脑废物清除通路 排列着星形胶质细胞，流入脑脊液并最终流入颈部淋巴结20-22。 系统可以消除中枢神经系统中的可溶性蛋白质和代谢物 系统，它可能与 Aβ 清除和 AD11 清除有关。 类淋巴系统的效率取决于脑脊液流量、脑血管搏动和 小鼠血管周围星形胶质细胞的水通道蛋白 4 (AQP4) 水通道的效率。 由于 AQP4 依赖的体积受损，类淋巴通路在衰老过程中似乎受到损害 flow23. 类淋巴系统在 Aβ 清除中的作用及其与 AD 的相关性是 主要基于对啮齿动物的研究24,23,25，这就是它仍然存在的原因之一 因此，需要检查类淋巴系统与 AD 的相关性。 而且，我们认为，在人脑中，这是最好的总体目标。 进行此检查的时间是在 Aβ 沉积的早期阶段之前和期间。 最后，我们拥有大量 30 岁至 65 岁的人类死后大脑 年龄，充分表征 AD 病变和组织完整性，并进行基因分型 这里提出的探索性和观察性研究是未来的基础。 类淋巴系统的机械检查及其与 AD 的相关性将在 培养的细胞和组织以及动物模型。