ApoE4, neurovascular injury and cognitive impairment

ApoE4、神经血管损伤和认知障碍

• 批准号: 10419353
• 负责人: Costantino Iadecola
• 金额: $ 84.69万
• 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/10419353
• 关键词: 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 - brain barrier anatomy; Blood Vessels; Blood flow; Bone Marrow; Brain; Brain Hypoxia-Ischemia; Carotid Stenosis; Carrier Proteins; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Chimera organism; Cognitive; Consensus; Corpus Callosum; Dementia; Development; Disease; Enzymes; Exhibits; Female; Fluorescence; Functional disorder; Gene Targeting; Genetic; Histopathology; Human; Hypoxia; Image; Impaired cognition; Individual; Inflammation; International; Knowledge; LDL-Receptor Related Protein 1; Lesion; Macrophage Activation; Mediating; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Oxidative Stress; 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; White Matter Disease; Work; apolipoprotein E-3; apolipoprotein E-4; autocrine; base; blood-brain barrier disruption; cerebrovascular; cognitive function; cognitive testing; experimental study; genetic risk factor; genetic variant; insight; lipid transport; macrophage; 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.

ApoE是一种富含于脑中的脂质转运蛋白，存在于三种等位基因变体（e2、e3、e4）中。 e4等位基因的纯合性（e4/e4）是阿尔茨海默病的主要遗传风险因素，但 ApoE 4携带者在血管和认知功能方面也增加了白色病变的风险。 损伤和阿尔茨海默病及相关痴呆症。皮质下和室周白色 物质损伤是与年龄相关的认知障碍的主要原因，但机制仍然存在 难以捉摸。深层的白色物质位于两个独立动脉区域的交界处， 非常容易缺氧缺血。ApoE 4携带者脑血流量减少，而 表达人ApoE 4的小鼠表现出调节ApoE 4表达的关键机制的深刻破坏。 将血液输送到大脑。这些发现提高了这种脑血管疾病的可能性， 失调使得深部白色物质更易受缺氧-缺血的影响。血管周围 巨噬细胞（PVM），脑内驻留的髓样细胞，紧密贴壁于脑外壁， 软脑膜血管和穿膜血管可产生ApoE，富含ApoE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衍生的ApoE 4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色的易感性增加 物质伤害。由于NOX 2是巨噬细胞中活性氧的主要来源， TRPM 2通道对巨噬细胞活化和神经血管功能障碍至关重要，我们将 也审视自己的角色。我们将检验以下假设：（a）PVM既是来源， 介导神经血管功能障碍的ApoE 4的靶标;（B）PVM TRPM 2通道和NOX 2 介导ApoE 4诱导的血管氧化应激和炎症，导致神经血管 功能障碍;（c）PVM衍生的ApoE 4负责增加对寡血 WM通过NOX 2和TRPM 2通道损伤。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。深白色 双侧颈动脉狭窄造成胼胝体物质损伤， 微弹簧圈使用了最先进的方法，包括3光子激发荧光成像 深白色物质和一种新的小鼠模型，使条件基因靶向PVM。 这些方法使我们能够评估深白色区的微血管灌注和损伤。 在PVM中ApoE 4、NOX 2或TRPM 2缺失的小鼠中，这些研究将提供洞察力 研究ApoE 4对白色物质损伤影响的潜在机制， 认知障碍和痴呆症的主要原因之一的新治疗目标。