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

研究脑脊液产生和循环在衰老和阿尔茨海默病中的作用

• 批准号: 10717111
• 负责人: Yu Luo
• 金额: $ 64.14万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717111
• 关键词: Ablation; Acceleration; Adult; Affect; Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Amyloid Proteins; Amyloid beta-42; Amyloid beta-Protein; Animal Disease Models; Animal Model; Animals; Antibody Therapy; Apoptotic; Area; Astrocytes; Atrophic; Behavioral; Biology; Blood; Blood Vessels; Brain; Brain Diseases; Cataloging; Cause of Death; Cell Death; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Choroid Plexus Epithelium; Circulation; Cognitive; Data; Development; Diphtheria Toxin; Disease; Disease Progression; Dose; Epithelial Cells; Etiology; Future; Goals; Health; Hippocampus; Homeostasis; Human; Immune; Impaired cognition; Impairment; Induction of Apoptosis; Infiltration; Inflammation; Intervention; Intracranial Pressure; Investigation; Knowledge; Link; Measures; Mediating; Metabolic; Modeling; Molecular; Motor; Mus; Neonatal; Nerve Degeneration; Neurocognitive; Neurons; Neurosciences; Outcome; Outcome Assessment; Pathogenesis; Pathologic; Pathology; Pathway interactions; Performance; Peripheral; Phenotype; Phosphorylation; Pilot Projects; Play; Prevalence; Process; Production; Protein Isoforms; Proteins; Research Proposals; Rodent; Role; Senile Plaques; Severities; Structure of choroid plexus; Symptoms; Synapses; System; Testing; Time; Transgenic Mice; Transplantation; Ventricular; Work; abeta accumulation; adult neurogenesis; age related; age related neuroinflammation; aged; aging brain; aging population; alpha synuclein; brain health; cognitive function; cytokine; diphtheria toxin receptor; extracellular; fluid flow; frontal lobe; functional outcomes; glial activation; glymphatic clearance; glymphatic flow; glymphatic system; in vivo; juvenile animal; mouse model; neurocognitive test; neurogenesis; neuroinflammation; neuron loss; neuronal survival; normal aging; novel; novel therapeutic intervention; pre-formed fibril; response; targeted treatment; tau Proteins; tau aggregation; tool; wasting; β-amyloid burden

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.

项目摘要 脉络丛（choroid plexus，CP）和脑脊液（cerebral spinal fluid，CSF）系统在脑的调节中起着多种积极的作用 体内平衡，最近已涉及大脑老化和认知功能。目前的工作重点是 对CP-CSF系统中的分子进行编目，并确定这些分子在大脑和大脑中的作用。 发育以及免疫-大脑相互作用。在多种CNS疾病中观察到CP萎缩， 最近的一项研究表明，将年轻的CSF移植到老年人的大脑中， 啮齿动物数量下降。通过血管周围间隙中的CSF流动破坏胶质淋巴循环的病症有 与减少淀粉样蛋白和tau蛋白从大脑中的清除有关。这些观察结果在动物和 人类脑部疾病表明CP-CSF系统在脑部疾病进展中起作用， 尤其是在衰老过程中。然而，尽管CP-CSF系统具有重要作用，但其在很大程度上 由于可用工具数量的限制， 精确地调节其功能。 通过使用我们最近发现的一种新的转基因小鼠品系，我们的项目将通过以下方式实现目标：（1） 建立了一种新的工具来消除小鼠衰老过程中的CP;（2）研究了CP的直接因果关系 在老年和阿尔茨海默病（AD）动物模型中，CSF生产在维持大脑健康方面的作用。 我们严格的初步数据表明：（1）该细胞系只能在CP中诱导细胞凋亡 上皮细胞，（2）CP消融导致心室容积部分至接近完全（50-90%）减少， 取决于药剂施用的剂量和时间，以及（3）CP的消融和CSF的损失导致 细胞外Aβ斑块和磷酸化细胞内蛋白的积累增加。这些 初步数据支持在AD动物模型中CSF产生在蛋白质清除中的直接和因果作用。 在本提案中，我们将首次研究CP消融对大脑衰老的剂量反应影响 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AD动物模型中CP/CSF降低的结果，包括 Aβ和tau AD模型。我们将重点关注AD相关病理学，例如细胞外淀粉样斑块 形成、细胞内tau神经元缠结（NFT）、神经变性、神经炎症和 认知功能 该项目为阐明CP-CSF在潜在脑老化中的作用提供了一个重要平台， 阿尔茨海默氏症相关的认知能力下降。通过建立一种新的工具，以任何期望的速度去除小鼠中的CP-CSF， 时间点（新生儿到成年），我们的项目将作出重大贡献和影响，促进 CP-CSF系统在神经科学和脑疾病领域的广泛研究。