Investigating the role of CSF production and circulation in aging and Alzheimer's disease

项目摘要 脉络丛(CP)和脑脊液(CSF)系统在脑调节中起着多种积极作用 动态平衡，最近被认为与大脑老化和认知功能有关。当前的工作重点是 对CP-CSF系统中的分子进行分类并确定这些分子在两个大脑中的作用 发育以及免疫与大脑的相互作用。在多种中枢神经系统疾病中观察到CP萎缩， 最近的一项研究表明，将年轻的脑脊液移植到老年大脑中可以逆转与年龄相关的认知 啮齿动物数量下降。通过血管周围间隙的脑脊液流动扰乱淋巴循环的情况有 与减少淀粉样蛋白和tau蛋白从大脑中的清除有关。这些在动物身上的观察和 人类大脑疾病表明CP-CSF系统在脑部疾病的进展或 恶化，尤指在衰老过程中。然而，尽管CP-CSF系统发挥着重要作用，但它在很大程度上 由于可用工具的数量有限，在神经科学领域仍然是一个未被充分探索的领域 精确地调节它的功能。 通过使用我们最近发现的一种新的转基因小鼠系，我们的项目将通过(1)实现这些目标 建立一种新的消融小鼠衰老过程中CP的工具及(2)研究其直接因果作用 在衰老和阿尔茨海默病(AD)动物模型中，脑脊液的产生在维持大脑健康方面的作用。 我们严格的初步数据表明：(1)该株系仅能诱导CP专一性的凋亡细胞死亡 上皮细胞，(2)CP消融导致部分至接近完全(50-90%)的脑室容量减少， 取决于给药的剂量和时间；(3)消融脑脊液和脑脊液会导致 胞外Aβ斑块和胞内磷酸化蛋白的积累增加。这些 初步数据支持脑脊液产生在AD动物模型蛋白质清除中的直接和因果作用。 在这项计划中，我们将首次研究脑壳核消融对脑老化的剂量反应效应。 特别关注与年龄相关的神经炎症、神经元存活、与年龄相关的神经发生下降 和认知功能。我们还将评估降低CP/CSF在AD动物模型中的结果，包括 Aβ和tau AD两种型号。我们将专注于AD相关的病理，如细胞外淀粉样斑块 形成，细胞内tau神经原纤维缠结(NFTs)，神经变性，神经炎症和 认知功能。 该项目为阐明CP-CSF在潜在的脑老化和脑损伤中的作用提供了重要的平台。 阿尔茨海默氏症相关的认知功能下降。通过建立一种新的工具来在任何需要的时候去除小鼠体内的CP-CSF 时间点(从新生儿到成人)，我们的项目将对促进 在神经科学和脑疾病的广泛主题中对CP-CSF系统的研究。

Project Summary The choroid plexus (CP) and cerebral spinal fluid (CSF) system serve multiple active roles in regulating brain homeostasis and have been recently implicated in brain aging and cognitive function. Current work is focused on cataloging molecules in the CP-CSF system and determining the role of these molecules in both brain development as well as immune-brain interactions. CP atrophy has been observed in multiple CNS disorders, and a recent study shows that transplantation of young CSF into aged brains reverses age-related cognitive decline in rodents. Conditions that disrupt glymphatic circulation via CSF flow in the perivascular space have been linked to decrease amyloid and tau protein clearance from the brain. These observations in animal and human brain disorders indicate that the CP-CSF system plays a role in brain disease progression or exacerbation, especially during aging. However, despite its important roles, the CP-CSF system has largely remained an under-explored field in neuroscience due to limitations in the number of available tools to precisely modulate its functions. By using a novel transgenic mouse line that we recently discovered, our project will address the goals by (1) establishing a new tool to ablate the CP in mice during the aging process and (2) study the direct causal role of CSF production in maintaining brain health during aging and in Alzheimer's disease (AD) animal models. Our rigorous preliminary data indicate that (1) this line can induce exclusive apoptotic cell death only in CP epithelial cells, (2) the CP ablation results in partial to near-complete (50-90%) reduction in ventricular volume, depending on the dose and timing of agent administration and (3) ablation of CP and loss of CSF leads to increased accumulation of both extracellular Aβ plaques and phosphorylated intracellular protein. These preliminary data support a direct and causal role of CSF production in protein clearance in AD animal models. In this proposal, for the first time, we will investigate the dose-response effects of CP ablation on brain aging with a special focus on age-related neuroinflammation, neuronal survival, age-related neurogenesis decline and cognitive function. We will also assess the outcome of CP/CSF reduction in animal models of AD including both Aβ and tau AD models. We will focus on AD-related pathology such as extracellular Amyloid plaque formation, intracellular tau neurofibrillary tangles (NFTs), neurodegeneration, neuroinflammation and cognitive function. This project provides an essential platform for elucidating the role of CP-CSF in underlying brain aging and Alzheimer's related cognitive decline. By establishing a new tool to remove CP-CSF in mice at any desired timepoint (neonatal to adulthood), our project will make significant contributions and impact on promoting studies of the CP-CSF system in a wide range of topics in neuroscience and brain diseases.