ApoE4, Neurovascular Injury and Cognitive Impairment

ApoE4、神经血管损伤和认知障碍

• 批准号: 10593979
• 负责人: Costantino Iadecola
• 金额: $ 83.07万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593979
• 关键词: Abbreviations; Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Apolipoprotein E; Astrocytes; Automobile Driving; Bilateral; Blood Vessels; Blood brain barrier dysfunction; Blood flow; Bone Marrow; Brain; Brain Hypoxia-Ischemia; Carotid Stenosis; Carrier Proteins; Cell secretion; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Chimera organism; Cognitive; Consensus; Corpus Callosum; Dementia; Development; Dichloromethylene Diphosphonate; Endowment; Enzymes; Exhibits; Female; Fluorescence; Functional disorder; Gene Targeting; Genetic; Histopathology; Human; Hypoxia; Image; Impaired cognition; Individual; Inflammation; Inflammatory; International; Knowledge; LDL-Receptor Related Protein 1; Leptomeninges; Lesion; Macrophage; Macrophage Activation; Mediating; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Neocortex; Oxidative Stress; Penetration; Perfusion; Photons; Play; Predisposition; Production; Reactive Oxygen Species; Regulation; Risk; Risk Factors; Role; Source; Testing; United States National Institutes of Health; Variant; Vascular Cognitive Impairment; Vascular Diseases; Ventricular; White Matter Disease; Work; apolipoprotein E-3; apolipoprotein E-4; autocrine; base; blood-brain barrier disruption; blood-brain barrier permeabilization; cerebrovascular; cognitive function; cognitive testing; experimental study; genetic risk factor; genetic variant; insight; ischemic injury; lipid transport; male; mouse model; neocortical; neurovascular; neurovascular injury; new therapeutic target; novel; novel strategies; receptor; sex; therapeutic target; vascular cognitive impairment and dementia; vascular factor; white matter; white matter damage; white matter injury

ApoE is a lipid transport protein enriched in brain and present in three allelic variants (e2, e3, e4). Homozygosity for the e4 allele (e4/e4) is the main genetic risk factor for Alzheimer’s disease, but ApoE4 carriers also have increased risk for white matter lesions in both vascular cognitive impairment and Alzheimer’s disease and related dementias. Subcortical and periventricular white matter damage is a major cause of age-related cognitive impairment, but the mechanisms remain elusive. Located at the borderzone between separate arterial territories, the deep white matter is highly vulnerable to hypoxia-ischemia. ApoE4 carriers have reduced cerebral blood flow, whereas mice expressing human ApoE4 exhibit a profound disruption of key mechanisms regulating the delivery of blood flow to the brain. These findings raise the possibility that such cerebrovascular dysregulation renders the deep white matter more susceptible to hypoxia-ischemia. Perivascular macrophages (PVM), brain resident myeloid cells closely apposed to the outer wall of cerebral pial and penetrating vessels, can produce ApoE, are enriched in ApoE receptors, and are a powerful source of vascular oxidative stress and inflammation. Therefore, we hypothesize that PVM-derived ApoE4 acts in an autocrine manner on PVM to produce vascular oxidative stress and inflammation, leading to neurovascular dysfunction and increased susceptibility to white matter injury. Since NOX2 is the main source of reactive oxygen species in macrophages and TRPM2 channels are critical for macrophage activation and neurovascular dysfunction, we will also examine their role. We will test the following hypotheses: (a) PVM are both a source and target of the ApoE4 mediating neurovascular dysfunction; (b) PVM TRPM2 channels and NOX2 mediate ApoE4-induced vascular oxidative stress and inflammation leading to neurovascular dysfunction; (c) PVM-derived ApoE4 is responsible for the increased susceptibility to oligemic WM damage through NOX2 and TRPM2 channels. Studies are conducted in young and old mice of both sexes with targeted replacement of mouse ApoE with human ApoE3 or 4. Deep white matter injury is produced in the corpus callosum by bilateral carotid artery stenosis using microcoils. Cutting-edge approaches are used, including 3-photon excited fluorescence to image the deep white matter and a novel mouse model enabling conditional gene targeting in PVM. These approaches allow us to assess microvascular perfusion and damage in the deep white matter in mice with ApoE4, NOX2, or TRPM2 deletion in PVM. These studies will provide insight into the mechanisms underlying the impact of ApoE4 on white matter damage and may unveil new therapeutic targets for one of the leading causes of cognitive impairment and dementia.

载脂蛋白E是一种富含于脑内的脂质运输蛋白，存在三种等位基因变体(e2、e3、e4)。 E4等位基因纯合(e4/e4)是阿尔茨海默病的主要遗传风险因素，但 ApoE4携带者也增加了认知血管白质损害的风险 损害和阿尔茨海默病以及相关的痴呆。皮质下和脑室周围白色 物质损伤是与年龄相关的认知障碍的主要原因，但其机制仍然 难以捉摸。位于不同动脉区域之间的交界处，深层白质是 极易受缺氧和缺血的影响。载脂蛋白E4携带者脑血流量减少，而 表达人载脂蛋白E4的小鼠表现出调控人类载脂蛋白E4的关键机制的深刻破坏 将血液输送到大脑。这些发现增加了这样一种可能性，即 调节失调使深层白质更容易受到缺氧缺血的影响。血管周围 巨噬细胞(PVM)是与大脑外壁紧密相对的脑内髓系细胞 膜和穿透血管，可产生载脂蛋白E，富含载脂蛋白E受体，是一种 血管氧化应激和炎症的强大来源。因此，我们假设 PVM来源的ApoE4以自分泌方式作用于PVM产生血管氧化应激 和炎症，导致神经血管功能障碍和对白人的易感性增加 物质损伤。由于NOX2是巨噬细胞内活性氧的主要来源， TRPM2通道是巨噬细胞激活和神经血管功能障碍的关键，我们将 也要审视他们的角色。我们将检验以下假设：(A)PVM既是源又是源 载脂蛋白E4介导神经血管功能障碍的靶点；(B)PVM、TRPM2通道和NOX2 介导载脂蛋白E4诱导的血管氧化应激和炎症导致神经血管 功能障碍；(C)PVM来源的ApoE4是导致少血症易感性增加的原因 通过NOX2和TRPM2通道造成的WM损伤。研究是在幼鼠和老年鼠身上进行的。 用人ApoE3或4.深白色靶向替换小鼠ApoE 用双侧颈总动脉狭窄造成的物质损伤 微线圈。使用了尖端的方法，包括三光子激发荧光成像 深白质和一种新的小鼠模型，使条件基因打靶在PVM。 这些方法使我们能够评估深白色的微血管灌注和损伤。 PVM中ApoE4、NOX2或TRPM2缺失的小鼠体内的物质。这些研究将提供洞察力 研究载脂蛋白E4对脑白质损伤影响的潜在机制，并可能揭示 针对认知障碍和痴呆症的主要原因之一的新治疗目标。