Understanding cellular architecture of the neurovascular unit and its function in the whole mouse brain

了解神经血管单元的细胞结构及其在整个小鼠大脑中的功能

• 批准号: 10401994
• 负责人: Yongsoo Kim
• 金额: $ 19.44万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401994
• 关键词: 3-Dimensional; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Anatomy; Animal Model; Antibodies; Applications Grants; Architecture; Area; Arteries; Atlases; Behavior assessment; Behavioral; Blood; Blood Vessels; Blood flow; Brain; Brain Mapping; Brain region; Cells; Cognitive; Cognitive deficits; Complex; Computer Analysis; Computer Simulation; Data; Disease; Disease Progression; Energy Supply; Etiology; Functional disorder; Future; Geometry; Grant; Hippocampus (Brain); Image; Impaired cognition; Injury; Label; Learning; Light; Link; Maps; Memory; Memory impairment; Metabolic; Methods; Microscopy; Morphology; Mus; Neurons; Pericytes; Permeability; Population; Public Health; Radial; Research; Resolution; Stains; Structure; Surface; Symptoms; Testing; Time; Tissues; United States National Institutes of Health; Vascular Diseases; Vascular blood supply; abeta accumulation; aging population; alanine aminopeptidase; base; behavior test; brain tissue; density; extracellular; innovation; microscopic imaging; mouse model; neurovascular; neurovascular unit; novel; overexpression; spatial memory; tool; wasting

Abstract Alzheimer’s disease (AD) is characterized by steep cognitive decline especially affecting learning and memory and has become a prominent public health concern driven by an increasing aging population. Prior research pinpointed accumulations of toxic cellular wastes such as amyloid beta (Aβ) as a primary pathophysiological hallmark in AD. Vascular disorders, which affect the brain’s ability to clear metabolic wastes and supply energy to neurons, have long been implicated in AD pathology. Microvessels which form complex networks provide large surface areas as a main interface between blood supply and brain tissues. Moreover, pericytes ensheathe microvessels allowing them to regulate blood flow and permeability. Emerging evidence suggests that the degeneration of microvessels and pericytes has been frequently observed in AD patients and animal models of AD. Moreover, Aβ accumulation and degeneration of vascular networks in AD occur in different brain regions at different rates across the whole brain. While strong evidence of the harmful interactions between Aβ accumulation and neurovascular function in AD exists, whether microvessel and pericyte injury occurs prior to Aβ accumulation and how interactions of Aβ with microvessels and pericytes change over time across different brain regions remains unclear. To discover this and more fully understand brain regional vulnerabilities, temporal affectations, and their consequences to brain function, we need to examine the quantitative distribution of microvessels and pericytes upon Aβ insults in relation to AD related behavioral changes. Therefore, we propose a two part hypothesis to examine the brain-wide changes of microvessels and pericyte populations in correlation with the emergence of Aβ accumulation in 5xFAD mice. SA1 will focus on the hypothesis that degeneration of microvessels occurs prior to Aβ accumulation and cognitive deficit while SA2 will test a hypothesis that degeneration of pericytes precede Aβ accumulation as the disease progresses. Both methods will utilize cutting- edge clearing and 3D immunolabeling, high-resolution light sheet fluorescent microscopy imaging, and advanced computational analysis to generate a first of its kind vascular/pericyte whole brain atlas in an AD mouse model with further analysis to resolve the interactions of microvessels/pericytes with Aβ paired with behavioral testing to assess cognitive deficits at the presymptomatic and early symptomatic stages of AD.

抽象的 阿尔茨海默氏病（AD）的特征是蒸汽认知能力下降，尤其影响学习和记忆 并已成为越来越多的人口老龄化的驱动的杰出公共卫生问题。先前的研究 精确的有毒细胞废物的积累，例如淀粉样β（Aβ）作为主要病理生理学 广告中的标志。血管疾病，会影响大脑清除代谢废物并供应能量的能力 对于神经元，长期以来一直隐含在AD病理学中。形成复杂网络提供的微型花序 大型表面积作为血液供应和脑组织之间的主要界面。此外，周细胞围绕 微血管使它们能够调节血流和渗透率。新兴证据表明 在AD患者和动物模型中经常观察到微血管和周细胞的变性 广告。此外，AD中血管网络的Aβ积累和变性发生在不同的大脑区域。 整个大脑的比率不同。而Aβ之间有害相互作用的有力证据 是否存在AD中的积累和神经血管功能，是否在微血管和周围损伤之前发生 Aβ积累以及Aβ与微血管和周细胞的相互作用如何随着时间的流逝而变化 大脑区域尚不清楚。发现这一点并更充分地了解大脑区域脆弱性，临时性 情感及其对大脑功能的后果，我们需要检查 与AD相关的行为变化有关的Aβ侮辱的微梗和周细胞。因此，我们提出 两个部分假设，以检查微血管和周细胞种群的大脑变化相关性的变化 随着5xFAD小鼠的Aβ积累的出现。 SA1将集中于以下假设 微血管发生在Aβ积累和认知缺陷之前，而SA2将检验一个假设，即 随着疾病的进展，周细胞的变性先于Aβ的积累。两种方法都将利用剪裁 - 边缘清除和3D免疫标签，高分辨率轻荧光显微镜成像和先进 计算分析以在AD鼠标模型中生成第一类血管/周围的全脑图 通过进一步的分析来解决微血管/周细胞与Aβ与行为测试配对的相互作用 评估AD的临时和早期症状阶段的认知缺陷。