ApoE4 and mechanisms of diffuse white matter injury

ApoE4 与弥漫性白质损伤的机制

• 批准号: 9355719
• 负责人: Costantino Iadecola
• 金额: $ 70.43万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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/9355719
• 关键词: Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Apolipoprotein E; Astrocytes; Bilateral; Blood Vessels; Blood flow; Bone Marrow; Brain; Brain Hypoxia-Ischemia; Carotid Stenosis; Cell surface; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; 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; Impaired cognition; Impairment; 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; Pathologic; Perfusion; Permeability; 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; artery stenosis; cerebrovascular; cognitive function; cognitive testing; experimental study; genetic risk factor; genetic variant; hemodynamics; imaging modality; in vivo; insight; light microscopy; lipid transport; macrophage; multiphoton imaging; neurophysiology; neurovascular; neurovascular coupling; new therapeutic target; novel; novel strategies; protein transport; response; sex; sulfated glycoprotein 2; therapeutic target; tool; vascular cognitive impairment and dementia; vascular factor; white matter; white matter damage; white matter injury

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.

皮质下和脑室周围白质损害是年龄相关认知的主要原因 损伤，但机制仍然难以捉摸。虽然与小船的联系 疾病导致慢性缺血是公认的，促进脑白质的因素 人们对破坏情况知之甚少。位于不同动脉区域之间的交界处 并由末梢小动脉供应，深层白质极易受到缺氧的影响。 缺血症。载脂蛋白E是一种富含在大脑中的脂质运输蛋白，存在于三种等位基因变体中 (2、3、4)。4等位基因纯合性(4/4)是阿尔茨海默病的主要遗传危险因素 疾病，但载脂蛋白E4携带者也增加了白质损害的风险 血管认知障碍和阿尔茨海默病。载脂蛋白E4携带者已经减少 脑血流量增加脑血管因素导致其增加的可能性 脑白质损伤的倾向。然而，目前尚不清楚ApoE4是否会扰乱至关重要的 脑血管机制，确保充足的脑血流，从而促进白色 物质缺血性损伤。血管周围巨噬细胞、骨髓源性细胞紧密对置 到脑小动脉外壁，富含载脂蛋白E受体，是一种强大的 活性氧和促炎介质的来源。因此，我们假设 载脂蛋白E4通过破坏关键的神经血管机制促进脑白质损伤 确保充足的脑灌流，这是一种由血管周围巨噬细胞通过 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扰乱了调节大脑的重要动态平衡机制 微循环；(B)血管周围巨噬细胞通过TRPM2参与功能障碍 (C)ApoE4加重缺氧缺血性脑白质损伤， 血管周围巨噬细胞介导的效应。研究是在幼鼠和老年鼠身上进行的。 用人的载脂蛋白E3或4.白质 双侧颈动脉狭窄造成的损伤发生在胼胝体。最先进的 研究神经血管调节的方法包括一种新的3光子成像技术。 一种方法，使我们第一次能够同时评估微血管灌注和 在活体内穹隆体白质的损伤。这些研究将提供对 载脂蛋白E4对白质损伤影响的潜在机制，并可能揭示新的 针对认知功能障碍的主要原因的治疗目标。