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

• 批准号: 10061520
• 负责人: Leon Maing Tai
• 金额: $ 38.92万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10061520
• 关键词: Address; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Apolipoprotein E; Apolipoproteins; Biochemical; Biological Assay; Blood; Blood - brain barrier anatomy; Blood capillaries; Brain; Bystander Effect; 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; LDL-Receptor Related Protein 1; Lead; 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-4; autocrine; base; blood-brain barrier function; brain endothelial cell; cognitive function; endothelial dysfunction; experimental study; genetic risk factor; improved; in vivo; neuroinflammation; paracrine; prevent; protective effect

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发挥着关键作用。 BBB 可防止不必要的 分子进入大脑并提供必需的营养物质和信号分子以满足高 神经元的能量需求。特殊的脑内皮细胞 (BEC) 是 BBB 功能的核心。 BEC 表达紧密连接蛋白，限制血液和 BEC 因子的细胞旁通透性 形成一个广泛的网络，每个神经元都由自己的毛细血管供电。目前的研究表明 BEC 功能障碍在衰老过程中普遍存在，导致更高的渗漏和更低的血管覆盖率。这些 变化可能以两种方式影响认知：1) 血浆蛋白的 BEC 泄漏量较高可能导致认知功能受损 直接或通过旁观者效应（例如神经胶质介导的神经炎症）影响神经元； 2) 下部容器 覆盖范围限制了神经元必需营养的供应。一个重要的问题是其程度和基础 衰老过程中认知能力下降的遗传因素和危险因素调节 BEC 功能的机制。这样的一位 因素是 APOE 基因型，因为与老年人中的 APOE3 相比，APOE4 与认知功能障碍相关 成年人。我们的体内数据支持 APOE4 与衰老过程中的 BEC 功能障碍相关，并且具有潜在的作用 底层机制已经显现。血管生成生长因子对于控制渗漏和 通过 BEC 功能行动维持船舶覆盖范围。我们的数据表明存在机械相互作用 存在于 APOE 和表皮生长因子 (EGF) 途径之间。具体来说，载脂蛋白 (apoE) E3 BEC 产生的信号通过 apoE 受体以自分泌/旁分泌样方式增加产量 EGF，从而改善 BEC 功能。然而，apoE4 会损害这一过程。基于这些 数据，我们建议检验 apoE4 受体信号传导失败导致 BEC 功能障碍的假设 EGF 可以改善这种功能障碍。我们进一步建议该机制有助于 BEC 在阿尔茨海默病（AD）患者中观察到的功能障碍。 APOE4 是散发性 AD 的最大遗传风险， 与 APOE3 相比，风险增加高达 12 倍，并且大脑中高水平的淀粉样蛋白-β (Aβ) 是一个主要因素 AD 的组成部分。我们的初步数据表明 Aβ 会加剧 APOE4 相关的 BEC 功能障碍。因此， 我们的实验将评估 APOE4 是否会增加 BEC 功能障碍以及 Aβ 是否会加剧这种功能障碍 体内功能失调。我们将研究 apoE 受体信号传导失败是否是 BEC 的根源 apoE4 功能障碍，并且 Aβ 加剧了这种破坏。最后我们来测试一下外设是否 施用 EGF 可以减少 BEC 和认知功能的缺陷。我们的研究表明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