Deciphering molecular mechanisms that underlie brain endothelial cell dysfunction with APOE4

用 APOE4 破译脑内皮细胞功能障碍的分子机制

基本信息

批准号：
10533753
负责人：
Leon Maing Tai
金额：
$ 37.32万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10533753
关键词：
Address Affect Age Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-Protein Apolipoproteins Biochemical Biological Assay Blood Blood - brain barrier anatomy Blood capillaries Brain Bystander Effect Cell Separation Cell physiology Cognition Cognitive Cognitive deficits Data Disease Elderly Elements Enzyme-Linked Immunosorbent Assay Epidermal Growth Factor Epidermal Growth Factor Receptor Failure Functional disorder Genetic Risk Genotype Goals Growth Factor Human Impaired cognition Impairment In Vitro Inflammation Learning Long-Term Effects Longevity Magnetic Resonance Imaging Mediating Memory Metabolism Modeling Molecular Mus Neurodegenerative Disorders Neurons Neurosciences Nutrient Pathway interactions Peripheral Permeability Plasma Plasma Proteins Play Process Production Proteins Public Health Receptor Activation Receptor Signaling Research Risk Risk Factors Role Signal Pathway Signal Transduction Signaling Molecule Synapses Testing Tight Junctions Tissues Treatment Factor Western Blotting age related aging brain angiogenesis apolipoprotein E-3 apolipoprotein E-4 autocrine blood-brain barrier function brain endothelial cell cognitive function endothelial dysfunction experimental study genetic risk factor improved in vivo neuroinflammation paracrine prevent protective effect receptor

项目摘要

ABSTRACT The blood brain barrier (BBB) plays a key role in maintaining brain integrity. The BBB prevents unwanted molecules from entering the brain and supplies essential nutrients and signaling molecules to meet the high- energy demand of neurons. Specialized brain endothelial cells (BECs) are central to the function of the BBB. BECs express tight junction proteins that limit paracellular permeability to factors from the blood and BECs form an extensive network with every neuron supplied by its own capillary. Current research has demonstrated that BEC dysfunction is prevalent in aging leading to both higher leakiness and lower vessel coverage. These changes may affect cognition in two ways: 1) Higher BEC leakiness to plasma proteins can lead to damage of neurons directly or through bystander effects (e.g. glial mediated neuroinflammation) and; 2) Lower vessel coverage limits the supply of essential nutrients to neurons. An important question is the extent and underlying mechanism(s) that genetic factors risk factors for cognitive decline in aging modulate BEC function. One such factor is APOE genotype, as APOE4 is associated with cognitive dysfunction compared to APOE3 in older adults. Our in vivo data supports that APOE4 is associated with BEC dysfunction in aging, and a potential underlying mechanism has emerged. Angiogenic growth factors are important for controlling leakiness and maintaining vessel coverage through actions on BEC function. Our data suggest a mechanistic interaction exists between APOE and epidermal growth factor (EGF) pathways. Specifically, that apolipoprotein (apoE) E3 produced by BECs signals in an autocrine/paracrine-like manner via apoE receptors to increase the production of EGF, resulting in improved BEC function. However, this process is impaired with apoE4. Based on these data, we propose to test the hypothesis that failure in apoE4 receptor signaling leads to BEC dysfunction and that EGF can ameliorate this dysfunction. We further propose that this mechanism contributes to BEC dysfunction observed in Alzheimer's disease (AD) patients. APOE4 is the greatest genetic risk for sporadic AD, increasing risk up to 12-fold compared to APOE3 and high levels of amyloid-β(Aβ) in the brain are a major component of AD. Our preliminary data suggest Aβ exacerbates APOE4 associated BEC dysfunction. Thus, our experiments will evaluate whether APOE4 increases BEC dysfunction and whether Aβ exacerbates this dysfunction in vivo. We will examine the possibility that a failure in apoE receptor signaling underlies BEC dysfunction with apoE4, and that this disruption is exacerbated by Aβ. Finally, we will test whether peripheral administration of EGF reduces deficits in BEC and cognitive function. Our studies would implicate apoE4 associated BEC dysfunction as an important pathway contributing to cognitive decline in both aging and AD

抽象的血脑屏障（BBB）在维持大脑完整性方面起着关键作用。 BBB阻止了不需要的分子进入大脑并提供必需的营养和信号分子以满足高神经元的能量需求。专门的脑内皮细胞（BEC）是BBB功能的核心。 BEC表达紧密连接蛋白将细胞细胞渗透性限制为血液和BEC的因素与自己的毛细管提供的每个神经元建立一个广泛的网络。当前的研究表明 BEC功能障碍在衰老导致较高的泄漏和较低的容器覆盖率方面普遍存在。这些变化可能以两种方式影响认知：1）更高的BEC泄漏对等离子体蛋白会导致损害神经元直接或通过旁观者效应（例如神经胶质介导的神经炎症）和； 2）较低的容器覆盖范围将基本营养素的供应限制为神经元。一个重要的问题是范围和基础机制，遗传因素衰老的认知下降危险因素调节了BEC功能。一个这样的因子是APOE基因型，因为APOE4与较老的APOE3相比与认知功能障碍有关成年人。我们的体内数据支持APOE4与衰老中的BEC功能障碍有关，并且潜力基本机制已经出现。血管生成因子对于控制泄漏和通过对BEC功能的行动来维持船舶覆盖范围。我们的数据表明机械互动 APOE和表皮生长因子（EGF）途径之间存在。具体而言，载脂蛋白（APOE）E3 由BEC信号以自分泌/旁分泌方式通过APOE接收器生产以增加生产 EGF，从而提高了BEC功能。但是，此过程受到APOE4的损害。基于这些数据，我们建议检验以下假设：APOE4受体信号传导导致BEC功能障碍和 EGF可以改善这种功能障碍。我们进一步提出，这种机制有助于BEC 在阿尔茨海默氏病（AD）患者中观察到的功能障碍。 APOE4是零星AD的最大遗传风险，与APOE3相比，大脑中的APOE3和高水平的淀粉样蛋白β（Aβ）的风险高达12倍是主要的 AD的组成部分。我们的初步数据表明Aβ加剧了APOE4相关的BEC功能障碍。那，我们的实验将评估APOE4是否增加了BEC功能障碍以及Aβ是否加剧了这一点体内功能障碍。我们将研究APOE接收器信号传导的失败基础的可能性 APOE4功能障碍，并且Aβ会加剧这种破坏。最后，我们将测试是否外围 EGF的给药减少了BEC和认知功能中的缺陷。我们的研究将暗示APOE4 相关的BEC功能障碍是导致衰老和AD认知能力下降的重要途径

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

APOE4 Promotes Tonic-Clonic Seizures, an Effect Modified by Familial Alzheimer's Disease Mutations.

DOI：
10.3389/fcell.2021.656521
发表时间：
2021
期刊：
Frontiers in cell and developmental biology
影响因子：
5.5
作者：
Lamoureux L;Marottoli FM;Tseng KY;Tai LM
通讯作者：
Tai LM

LPC-DHA/EPA-Enriched Diets Increase Brain DHA and Modulate Behavior in Mice That Express Human APOE4.

DOI：
10.3389/fnins.2021.690410
发表时间：
2021
期刊：
Frontiers in neuroscience
影响因子：
4.3
作者：
Scheinman SB;Sugasini D;Zayed M;Yalagala PCR;Marottoli FM;Subbaiah PV;Tai LM
通讯作者：
Tai LM