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

项目摘要 大量证据表明可溶性Aβ寡聚体具有神经毒性1 -5， 可溶性Aβ的清除是迟发性AD的一个重要病理机制， 通过观察到Aβ进入脑脊液（CSF）的通道减少， AD 6与AD患者CSF中Aβ水平降低7，8，9，10.的机制 从脑中清除细胞外Aβ是多方面的11，包括局部酶 降解12、穿过血脑屏障（BBB）13-16或经由CSF 17运输。的相对 这些不同系统对Aβ清除的贡献还不完全清楚，尽管 BBB系统似乎占主导地位。然而，最近，胶质淋巴系统已经被 参与这一过程，可能除了BBB机制15，16。胶质淋巴 系统18，19被提议作为由血管周围隧道组成的脑废物清除途径 衬有星形胶质细胞，其流入CSF并最终进入颈部淋巴结20 -22。这 系统允许从中枢神经系统中消除可溶性蛋白质和代谢物 它可能与Aβ清除和AD 11的发生有关。的间隙 胶质淋巴系统的效率取决于脑脊液流量、脑血管搏动和 血管周围星形胶质细胞的水通道蛋白-4（AQP 4）水通道23.在小鼠中， 由于AQP 4依赖性体积受损，胶质淋巴通路在衰老中出现受损 流动23.胶质淋巴系统在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，这也是为什么它仍然存在的原因之一 有争议的26.因此，需要检查胶质淋巴系统与AD的相关性 这也是这个计划的总体目标此外，我们认为， 进行这项检查的时间是在Aβ沉积的早期阶段之前和期间。本 最后，我们有大量的人类死后大脑，从30岁到65岁的个体， 岁，其完全表征AD病变和组织完整性，并且基因分型为 ApoE这里提出的探索性和观察性研究是未来研究的基础。 胶质淋巴系统的机制检查及其与AD的相关性将在 培养的细胞和组织以及动物模型。

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.