ApoE4 and mechanisms of diffuse white matter injury

ApoE4 与弥漫性白质损伤的机制

• 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
• 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' 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

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色物质损害是年龄相关认知功能障碍的主要原因 但机制仍然难以捉摸。尽管与小型船只的联系 导致慢性缺血的疾病是公认的，促进白色物质的因素 对伤害了解甚少。位于各大动脉区域之间的边界地带 并由终末小动脉供应，深层白色物质非常容易缺氧- 缺血ApoE是一种富含于脑中的脂质转运蛋白，以三种等位基因变体存在 （1992，1993，1994）。Alzheimer 4等位基因的纯合性（Alzheimer 4/Alzheimer 4）是阿尔茨海默病的主要遗传风险因素。 疾病，但ApoE 4携带者也有增加的风险，白色物质病变的设置， 血管性认知障碍和阿尔茨海默病ApoE 4携带者减少 脑血流量增加的可能性，脑血管因素有助于其增加 倾向于白色物质损害。然而，目前尚不清楚ApoE 4是否会破坏重要的 脑血管机制，确保足够的脑灌注，从而促进白色 缺血性损伤。血管周围巨噬细胞、骨髓源性细胞紧密贴壁 大脑小动脉外壁的血管壁富含ApoE受体，是一种强有力的 活性氧和促炎介质的来源。因此，我们假设 ApoE 4通过破坏关键的神经血管机制促进白色物质损伤， 确保足够的脑灌注，血管周围巨噬细胞通过 氧化应激和炎症。由于TRPM 2通道参与巨噬细胞的增殖， 激活和神经血管功能障碍，我们也将研究它们的作用。我们将测试 以下假设：（a）ApoE 4破坏了调节脑内 微循环;（B）血管周围巨噬细胞通过TRPM 2促进功能障碍 通道和ApoE受体;（c）ApoE 4加重缺氧缺血性白色物质损伤， 由血管周围巨噬细胞介导的作用。研究在年轻和年老的老鼠中进行 用人ApoE 3或4靶向替换小鼠ApoE。白色物质 双侧颈动脉狭窄在胼胝体中产生损伤。State-of-the-art 方法用于研究神经血管调节，包括一种新的3光子成像 这种方法使我们能够第一次同时评估微血管灌注， 在体内胼胝体的白色物质的损伤。这些研究将提供深入了解 ApoE 4对白色物质损伤影响的潜在机制，并可能揭示新的 认知功能障碍的主要原因的治疗目标。