Investigating brain clearance mechanisms involved in the removal of pathological proteins associated with neurodegenerative disease, and their potenti

清除大脑废物长期以来一直是神经科学领域的热门话题；大脑是最耗能和产生废物的器官，但却没有用于清除废物的经典淋巴系统。淋巴系统最接近的部分位于硬脑膜内，但这些血管不进入脑组织，因此其他清除废物或将废物输送到这些血管的机制肯定在发挥作用。解开大脑中的废物清除过程可以为了解大脑健康、疾病的发病机制和进展提供见解，并提供新的治疗靶点。淋巴系统是一种血管旁废物清除系统，包括清除脑组织深处的废物。已经发现它可以清除与神经退行性疾病病理有关的普恩样蛋白，即与阿尔茨海默病有关的β-淀粉样蛋白，与多种痴呆有关的tau蛋白，以及与帕金森氏病和路易体疾病有关的α-突触核蛋白。在这一途径中，脑脊液(CSF)沿着穿透小动脉(从软膜动脉发出的分支)进入大脑，通过血管旁间隙，在血管内皮细胞和包裹血管的星形细胞终足之间。脑脊液通过星形细胞终足和水通道之间的间隙进入脑实质的间隙，水通道蛋白-4位于终足。液体的流入将充满废物的间质液体推向静脉血管旁间隙，然后到达脑膜和颈部淋巴管，以清除体内。淋巴系统可以被药物上调和抑制，在神经退行性疾病状态下有可能成为一个可行的治疗靶点。脑淋巴管内皮细胞是与脑膜血管密切相关的单个细胞，发现于斑马鱼的软脑膜中，位于存在脑膜淋巴管的硬脑膜下方。这些细胞是非管腔的，所以不会形成血管，但确实表达淋巴管细胞标志物(prox1a、vgfr3、LYVE1)。这些细胞可以内化大分子，包括β-淀粉样蛋白(1-40，以及1-42的单体和寡聚形式)。大分子的内吞作用依赖于甘露糖受体1a，甘露糖受体1a被描述为模式识别受体，对病原体的识别、结合和内化至关重要。这是对BLEC进行药理操作的一个要点。在老鼠和人类身上也发现了这些细胞，它们可能为理解废物如何从大脑中清除，或者大脑如何通过监测保持健康提供了另一个谜题。淋巴系统功能障碍或BLECs可能与神经退行性疾病的进展和病理性蛋白质堆积有关。单独了解这些系统，以及它们之间可能的联系，可以增强我们对有关神经退行性疾病和其他神经疾病的脑废物清除的理解。在我的博士项目中，我打算与哈里森和里赫尔实验室合作，使用斑马鱼和小鼠模型以及人体组织，以了解这些清除机制之间的联系及其与疾病的关系。

Brain waste clearance has long been a popular topic of discussion within neuroscience; the brain is the most energy-consuming and waste-producing organ yet does not have a classical lymphatic system for waste removal. The closest part of the lymphatic system lies within the dural meninges, but these vessels do not enter the brain tissue, thus other mechanisms of waste clearance or transport of waste to these vessels must be at play. Disentangling waste clearance processes in the brain could provide insights into brain health, disease pathogenesis and progression, and provide novel therapeutic targets. The glymphatic system is a paravascular waste clearance system which encompasses clearance in deep brain tissue. It has been found to clear prion-like proteins involved in neurodegenerative disease pathologies, namely beta-amyloid associated with Alzheimer's disease, tau associated with numerous dementias, and alpha synuclein associated with Parkinson's disease and Lewy body disorders. In this pathway, cerebrospinal fluid (CSF) follows penetrating arterioles (branching from pial arteries) into the brain, via the paravascular space, between the blood vessel endothelium and the astrocytic endfeet which ensheath it. The CSF moves into the interstitial space of the brain parenchyma through gaps in between the astrocytic endfeet and the water channel, aquaporin-4, which is localized at the endfeet. Inflow of fluid pushes waste-filled interstitial fluid towards the venous paravascular space, and then to the meningeal and cervical lymphatics for clearance out of the body. The glymphatic system can be upregulated and inhibited pharmacologically and has the potential to be an viable therapeutic target in neurodegenerative disease states.Brain lymphatic endothelial cells (BLECs) are single cells in close association with meningeal blood vessels, found in the leptomeninges of zebrafish, sitting below the dura where the meningeal lymphatic vessels exist. The cells are non-lumenised, so do not form vessels, but do express lymphatic cell markers (prox1a, vgfr3, lyve1). These cells can internalize macromolecules, including beta-amyloid (1-40, and also monomeric and oligomeric forms of 1-42). Endocytosis of macromolecules is dependent on the mannose receptor 1a, which is describes as a pattern-recognition receptor, crucial for identification, binding and internalization of pathogens. This is a point of pharmacological manipulation of BLECs. These cells have also been found in mice and humans and could provide another part of the puzzle to understanding how waste is cleared from the brain, or how the brain maintains its health through surveillance. Dysfunction of the glymphatic system or BLECs could be linked to neurodegenerative disease progression and pathological protein accumulation. Understanding these systems individually, and possible connections between them, could enhance our understanding of brain waste clearance regarding neurodegenerative diseases and other neurological conditions. In my PhD project, I intend to use zebrafish and mouse models, as well as human tissue, in collaboration with the Harrison and Rihel labs, to understand the links between these clearance mechanisms and their relationship to disease.