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

研究清除与神经退行性疾病相关的病理蛋白所涉及的大脑清除机制及其潜力

• 批准号: 2720592
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2720592
• 关键词: Investigating; brain; clearance; mechanisms; involved

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.

脑废物清除长期以来一直是神经科学领域讨论的热门话题。大脑是最消耗能量和产生废物的器官，但没有经典的淋巴系统来清除废物。淋巴系统最近的部分位于硬脑膜内，但这些血管不进入脑组织，因此废物清除或将废物运输到这些血管的其他机制必须发挥作用。解开大脑中废物清除过程可以深入了解大脑健康、疾病发病机制和进展，并提供新的治疗靶点。类淋巴系统是一种血管旁废物清除系统，包括深部脑组织的清除。人们发现它可以清除与神经退行性疾病病理相关的朊病毒样蛋白，即与阿尔茨海默病相关的 β-淀粉样蛋白、与多种痴呆症相关的 tau 蛋白以及与帕金森病和路易体疾病相关的 α 突触核蛋白。在此通路中，脑脊液 (CSF) 跟随穿透性小动脉（从软脑膜动脉分支），通过血管内皮和包裹血管内皮的星形细胞端足之间的血管旁间隙进入大脑。脑脊液通过星形胶质细胞末足和位于末足的水通道 aquaporin-4 之间的间隙进入脑实质的间隙空间。液体的流入将充满废物的间质液推向静脉血管旁间隙，然后推向脑膜和颈部淋巴管以清除体外。类淋巴系统可以在药理学上上调和抑制，并有可能成为神经退行性疾病状态下可行的治疗靶点。脑淋巴内皮细胞（BLEC）是与脑膜血管密切相关的单细胞，存在于斑马鱼的软脑膜中，位于脑膜淋巴管所在的硬脑膜下方。这些细胞没有内腔，因此不形成血管，但表达淋巴细胞标记物（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，它被描述为一种模式识别受体，对于病原体的识别、结合和内化至关重要。这是 BLEC 药理学操作的要点。这些细胞也在小鼠和人类身上发现，可以为理解大脑如何清除废物，或大脑如何通过监视保持健康提供谜题的另一部分。类淋巴系统或 BLEC 的功能障碍可能与神经退行性疾病的进展和病理性蛋白质积累有关。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神经退行性疾病和其他神经系统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来了解这些清除机制及其与疾病的关系之间的联系。