Macroscopic distribution pathways of apoE in CNS

apoE在CNS中的宏观分布途径

• 批准号: 8928812
• 负责人: RASHID DEANE
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928812
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animals; Apolipoprotein E; Arteries; Astrocytes; Binding; Blocking Antibodies; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebrospinal Fluid; Cholesterol; Data; Dendritic Spines; Diffusion; Disease; Distant; Failure; Glutamates; Glutamine; Health; Homeostasis; Human; Intercellular Fluid; LDL-Receptor Related Protein 1; Lip structure; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Maintenance; Metabolic; Metabolic Pathway; Mus; Neuraxis; Neurocognitive; Neurons; Pathway interactions; Pattern; Peripheral; Play; Production; Protein Isoforms; Proteins; Radial; Risk Factors; Role; Source; Structure of choroid plexus; Supporting Cell; Synapses; System; Testing; Veins; Venous; age effect; age related; analytical tool; apolipoprotein E-1; apolipoprotein E-3; apolipoprotein E-4; aquaporin 4; density; improved; lipid metabolism; novel; prevent; receptor; relating to nervous system; research study; solute; therapeutic target

DESCRIPTION (provided by applicant): Apolipoprotein E (apoE) is essential for the transport and metabolism of lipids in the CNS. Of the three apoE isoforms (E2, E3 and E4), E4 is a major risk factor for Alzheimer's disease (AD). Under normal conditions, it is recognized that the highly specialized mature neurons outsource apoE production to astrocytes, but the mechanism for apoE delivery to neurons remains unclear. Recently, a brain-wide pathway that facilitates convective flow of interstitial fluid (ISF) was shown to play a major role in clearance of by-products of neural activity, including amyloid-beta. This perivascular system of cerebrospinal fluid (CSF) channels-termed the glymphatic system- allows solute exchange with parenchymal ISF by three main pathways: (1) influx of CSF via the peri-arterial space, (2) astrocytic aquaporin 4 (AQP4)-dependent convective flow of ISF through the brain parenchyma, and (3) efflux via para-venous clearance. We propose to test the idea that the glymphatic system also serves as a brain-wide distribution path for the delivery of essential substances to neurons. We choose to test this concept for apoE, since brain apoE is independent of peripheral apoE, CSF could be a source of apoE and because lipid dysregulation is a major risk factor for AD. Our pilot data show, (1) that lipidated apoE (lip-apoE) was circulated by the glymphatic system and entered brain ISF via peri-arterial influx; (2) unexpectedly, fluorescently-tagged lip-apoE was distributed in an isoform specific pattern of zones around penetrating arteries (E4< E3 < E2), and (3) glymphatic distribution of apoE was sharply reduced in aging and in Aqp4-/- mice. We hypothesize that the glymphatic system is critical for brain-wide distribution of apoE to neurons and that age-related failure of this system deprives neurons, located distant to the arteries, access to cholesterol and essential lipids needed for formation and maintenance of synapses. We propose to generate a basic analysis on this novel brain-wide pathway of apoE distribution by an experimental approach centered on the following objectives: Aim 1 will characterize the macroscopic delivery and distribution of apoE isoforms. Aim 2 will assess the effect of aging and AQP4 on the macroscopic distribution of apoE isoforms in conditional inducible Aqp4-/- and control mice. Aim 3 will determine the role of apoE receptors in the macroscopic apoE delivery using specific receptor blocking antibodies. We hypothesize that apoE receptors trap apoE with different efficacy dependent on the apoE isoforms, resulting in the differential distribution profiles, and that reduced peri-arterial convective CSF influx in aging and Aqp4-/- animals will reduce apoE distribution. The implication of the proposed concept is that failure of brain-wide glymphatic distribution of apoE contributes to apoE isoform specific related disorders, including cerebral amyloid angiopathy (CAA) and AD. Our hope is that these studies will generate entirely novel targets for slowing or even preventing AD related neurocognitive decline by improving the glymphatic distribution of apoE, a target that has been ignored so far.

性状（由申请方提供）：载脂蛋白E（apoE）对于CNS中脂质的转运和代谢至关重要。在三种apoE亚型（E2、E3和E4）中，E4是阿尔茨海默病（AD）的主要危险因素。在正常情况下，人们认识到， 特化的成熟神经元将apoE生产外包给星形胶质细胞，但apoE递送到神经元的机制仍不清楚。最近，促进间质液（ISF）对流的全脑通路被证明在清除神经活动的副产物（包括淀粉样蛋白β）中发挥重要作用。脑脊液（CSF）通道的这种血管周围系统-称为胶质淋巴系统-允许通过三种主要途径与实质ISF进行溶质交换：（1）CSF通过动脉周围空间流入，（2）ISF通过脑实质的星形胶质细胞水通道蛋白4（AQP 4）依赖性对流，以及（3）通过静脉旁清除流出。我们建议测试的想法，胶质淋巴系统也作为一个大脑范围内的分配路径的基本物质的神经元的交付。我们选择测试apoE的这一概念，因为脑apoE独立于外周apoE，CSF可能是apoE的来源，并且因为脂质失调是AD的主要危险因素。我们的初步数据显示，（1）脂化apoE（lip-apoE）通过胶质淋巴系统循环，并通过动脉周围流入进入脑ISF;（2）出乎意料的是，荧光标记的lip-apoE以穿通动脉周围区域的同种型特异性模式分布（E4< E3 < E2），和（3）apoE的胶质淋巴分布在衰老和Aqp 4-/-小鼠中急剧减少。我们假设胶质淋巴系统对于apoE向神经元的全脑分布是至关重要的，并且该系统的年龄相关性故障剥夺了位于远离动脉的神经元获得突触形成和维持所需的胆固醇和必需脂质的途径。我们建议通过实验方法对这种新型的apoE分布的全脑途径进行基本分析，该方法集中于以下目标：目的1将表征apoE亚型的宏观递送和分布。目的2将评估衰老和AQP 4对条件诱导型Aqp 4-/-和对照小鼠中apoE亚型宏观分布的影响。目的3将使用特异性受体阻断抗体确定apoE受体在宏观apoE递送中的作用。我们假设apoE受体以不同的功效捕获apoE，这取决于apoE亚型，从而导致差异分布特征，并且在衰老和Aqp 4-/-动物中减少动脉周围对流CSF流入将减少apoE分布。所提出的概念的含义是，apoE的全脑胶质淋巴分布的失败有助于apoE亚型特异性相关疾病，包括脑淀粉样血管病（CAA）和AD。我们希望这些研究将产生全新的靶点，通过改善apoE的胶质淋巴分布来减缓甚至预防AD相关的神经认知功能下降，这是一个迄今为止被忽视的靶点。