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

项目总结 有大量证据表明，可溶性A-β寡聚体具有神经毒性1-5，并损害 清除可溶性A-β是晚发性AD的一个重要病理机制 β进入脑脊液的通道减少的观察支持 AD患者7、8、9、10脑脊液中A-β水平的降低 细胞外Aβ从脑中的清除是多方面的，包括局部酶 降解12，运输通过血脑屏障(BBB)13-16，或通过CSF17。相对的 这些不同的系统对β许可的贡献还没有完全了解，尽管 血脑屏障系统似乎占主导地位。然而，最近，臀部系统已经被 与这一过程有关，可能是血脑屏障机制之外的15，16。 系统18，19被认为是由血管周围隧道组成的脑废物清除途径 星形胶质细胞排列成行星形细胞，流入脑脊液，最终进入颈淋巴结节20-22。这 系统允许清除中枢神经系统中的可溶性蛋白质和代谢物。 它可能与Aβ清除和AD11的发展有关。通行证 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水通道AQP4。在小鼠身上， 由于AQP4依赖的大块受损，衰老过程中的淋巴通路似乎受到了损害 流程23.淋巴系统在清除β中的作用及其与AD的相关性是 主要基于对啮齿动物24、23、25的研究，这是它仍然存在的原因之一 有争议的26.因此，需要检查淋巴系统与AD的相关性 在人脑中，这是这项提议的总体目标。此外，我们认为最好的 进行这项检查的时间是在Aβ沉积之前和早期阶段。对这件事 最后，我们有大量的人类尸检大脑，年龄从30岁到65岁 年龄，充分表现为AD损害和组织完整性，并对 APOE.本文提出的探索性研究和观察性研究是未来研究的基础。 对舌管系统的机械检查及其与AD的相关性将于#年进行 培养细胞和组织，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.