ApoE4 and mechanisms of diffuse white matter injury

ApoE4 与弥漫性白质损伤的机制

基本信息

批准号：
9264693
负责人：
Costantino Iadecola
金额：
$ 70.73万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264693
关键词：
Age-associated memory impairment Aging Alleles Alzheimer&apos s Disease Apolipoprotein E Astrocytes Bilateral Blood Vessels Blood flow Bone Marrow Brain Brain Hypoxia-Ischemia Carotid Stenosis Carrier Proteins Cell surface Cells Cerebrovascular Circulation Cerebrum Chimera organism Chronic Cognitive Common carotid artery Corpus Callosum Data Dementia Development Dichloromethylene Diphosphonate Diffuse Disease Elderly Electron Microscopy Electrophysiology (science)Emerging Technologies Endothelium Functional disorder Funding Homeostasis Human Hypoxia Image Impaired cognition Individual Inflammation Injury Ischemia Knowledge LDL-Receptor Related Protein 1 Lesion Macrophage Activation Mediating Mediator of activation protein Microcirculation Microglia Microscopy Microvascular Dysfunction Molecular Monitor Mus Outcome Oxidative Stress Perfusion Phagocytes Photons Play Predisposition Process Reactive Oxygen Species Regulation Rest Risk Risk Factors Role Source Testing Time Tissues United States National Institutes of Health Variant Vascular Cognitive Impairment Vascular Diseases White Matter Disease Work apolipoprotein E-3 apolipoprotein E-4 arteriole base cerebrovascular cognitive function cognitive testing genetic risk factor genetic variant hemodynamics imaging modality in vivo insight light microscopy lipid transport macrophage neurophysiology neurovascular neurovascular coupling new therapeutic target novel novel strategies research study response sex sulfated glycoprotein 2 therapeutic target tool vascular factor white matter white matter damage white matter injury

项目摘要

Subcortical and periventricular white matter damage is a major cause of age-related cognitive impairment, but the mechanisms remain elusive. Although the association with small vessel disease leading to chronic ischemia is well recognized, the factors promoting white matter damage are poorly understood. Located at the borderzone between separate arterial territories and supplied by terminal arterioles, the deep white matter is highly vulnerable to hypoxia- ischemia. ApoE is a lipid transport protein enriched in brain and present in three allelic variants (2, 3, 4). Homozygosity for the 4 allele (4/4) is the main genetic risk factor for Alzheimer's disease, but ApoE4 carriers also have increased risk for white matter lesions in the setting of both vascular cognitive impairment and Alzheimer's disease. ApoE4 carriers have reduced cerebral blood flow raising the possibility that cerebrovascular factors contribute their increased propensity to white matter damage. However, it remains unclear whether ApoE4 disrupts vital cerebrovascular mechanisms that assure adequate cerebral perfusion thereby promoting white matter ischemic injury. Perivascular macrophages, bone marrow derived cells closely apposed to the outer wall of cerebral arterioles, are enriched in ApoE receptors and are a powerful source of reactive oxygen species and proinflammatory mediators. Therefore, we hypothesize that ApoE4 promotes white matter damage by disrupting critical neurovascular mechanisms that assure adequate cerebral perfusion, an effect mediated by perivascular macrophages through oxidative stress and inflammation. Since TRPM2 channels are involved in macrophage activation and neurovascular dysfunction, we will also examine their role. We will test the following hypotheses: (a) ApoE4 disrupts vital homeostatic mechanisms regulating the cerebral microcirculation; (b) perivascular macrophages contribute to the dysfunction through TRPM2 channels and ApoE receptors; (c) ApoE4 exacerbates hypoxic-ischemic white matter damage, an effect mediated by perivascular macrophages. Studies are conducted in young and old mice of both sexes with targeted replacement of mouse ApoE with human ApoE3 or 4. White matter injury is produced in the corpus callosum by bilateral carotid artery stenosis. State-of-the-art approaches are used to study neurovascular regulation, including a novel 3-photon imaging method enabling us, for the first time, to simultaneously assess microvascular perfusion and damage in the white matter of the corpus callosum in vivo. These studies will provide insight into the mechanisms underlying the impact of ApoE4 on white matter damage, and may unveil new therapeutic targets for a leading cause of cognitive dysfunction.

皮质下和周围白质损害是与年龄相关的认知的主要原因损害，但这些机制仍然难以捉摸。虽然与小船的关联导致慢性缺血的疾病被广泛认可，促进白质的因素损害知之甚少。位于单独伪影之间的边界区域并由末端Artiolles提供，深层白质非常容易受到缺氧的影响。缺血。 APOE是一种富含大脑的脂质转运蛋白，并存在于三种等位基因变体中（2，3，4）。 4等位基因（4/4）的纯合性是阿尔茨海默氏症的主要遗传危险因素疾病，但在血管认知障碍和阿尔茨海默氏病。 APOE4载体减少了脑血流增加了脑血管因素的可能性增加白质损害的倾向。但是，尚不清楚APOE4是否破坏了重要脑血管机制可确保足够的脑灌注，从而促进白色物质缺血性损伤。血管周围巨噬细胞，骨髓衍生的细胞紧密应用到脑artiolles的外墙，富含Apoe接收器，是一个强大的活性氧和促炎介质的来源。因此，我们假设 APOE4通过破坏关键神经血管机制来促进白质损害确保足够的脑灌注，这是由周围巨噬细胞介导的作用氧化应激和炎症。由于TRPM2通道参与巨噬细胞激活和神经血管功能障碍，我们还将检查它们的作用。我们将测试以下假设：（a）APOE4破坏了调节大脑的重要稳态机制微循环；（b）周围巨噬细胞通过TRPM2导致功能障碍通道和APOE受体；（c）APOE4加剧了缺氧 - 缺血性白质损害，血管周围巨噬细胞介导的作用。研究是在老鼠和老鼠中进行的用人apoe3或4的靶向替换鼠标APOE的两性。双侧颈动脉伪影在call体中造成损伤。最先进的方法用于研究神经血管调节，包括一种新型的3光子成像方法使我们第一次可以轻松评估微血管灌注和体内call体的白色物质的损害。这些研究将提供有关 APOE4对白质损害的影响的基础机制，并可能揭示新的认知功能障碍的主要原因的治疗靶标。