The Role of PAI-1 in Cerebral Microvascular Dysfunction and the Development of Alzheimer’s Disease Neuropathology

PAI-1 在脑微血管功能障碍和阿尔茨海默病发展中的作用 神经病理学

• 批准号: 10314556
• 负责人: Daniel A Lawrence
• 金额: $ 67.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10314556
• 关键词: Accounting; Affect; Affinity Chromatography; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid deposition; Behavioral; Blood Vessels; Blood flow; Brain; Cardiovascular system; Cerebrum; Clinical; Cognition; Cognitive deficits; Complex; Data; Dementia; Development; Disease Progression; Endothelial Cells; Enzyme Precursors; Enzymes; Etiology; Failure; Fibrinolysis; Functional disorder; Gene Expression; Genes; Hemostatic function; Hypertension; Impaired cognition; Inflammation; Inflammatory; Light; Link; Literature; Methods; Microvascular Dysfunction; Modeling; Modernization; Morphology; Mus; Nature; Neurofibrillary Tangles; Neurosciences; Onset of illness; Other Genetics; Outcome; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Pharmacology; Phenotype; Plasmin; Plasminogen; Plasminogen Activator; Plasminogen Activator Inhibitor 1; Plasminogen Inactivators; Play; Reporting; Ribosomes; Risk Factors; Role; Senile Plaques; Severities; Severity of illness; Signal Transduction; Synapses; System; Tauopathies; Testing; Tissues; Transgenic Organisms; Translating; Urokinase; Vascular Diseases; Vascular remodeling; abeta deposition; angiogenesis; base; cardiovascular disorder risk; cardiovascular risk factor; comorbidity; diagnostic biomarker; extracellular; hyperphosphorylated tau; improved; improved outcome; inhibitor/antagonist; mouse model; neuron loss; neuropathology; neurovascular; neurovascular coupling; novel; relating to nervous system; response to injury; transcriptome sequencing; translatome; vascular abnormality; vascular injury; wound; wound healing

ABSTRACT The pathophysiology of Alzheimer’s disease (AD) is complex and represents one of the most difficult and pressing challenges facing modern neuroscience. Intracellular neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau and senile plaques consisting of aggregated extracellular amyloid beta (Aβ) are the hallmark pathological features of AD. However, it is clear that other factors likely contribute to the neural system failure and cognitive impairments associated with AD. Mounting clinical and experimental data suggest that cardiovascular disease (CVD) risk factors that promote vascular remodeling and dysfunction are associated with cognitive impairment, and are significant risk factors for the development of AD dementia. These studies include observations directly linking pathways associated with vascular injury such as hemostasis, angiogenesis, and hypertension to AD, leading to the hypothesis that CVD risk factors may act via common mechanisms to promote AD development or progression. For example, current data show that plaques, tangles, and CVD risk factors all upregulate expression of plasminogen activator inhibitor 1 (PAI-1), an independent CVD risk factor. Recent studies also suggest that PAI-1 may be a diagnostic biomarker and/or a risk factor for clinical AD, and PAI-1 expression increases with age, the most significant risk factor for AD dementia. PAI-1 is best understood for its role regulating fibrinolysis and wound, and in mouse models of AD PAI-1 deficiency is correlated with improved outcomes. In preliminary data presented here in the 5XFAD amyloidogenic mouse model we find that significant vascular remodeling occurs concurrently with amyloid plaque development and cognitive impairment. These changes are associated with reductions in cortical blood flow and increased PAI-1 expression. RNA-Seq and pathway analysis identify highly significant increases in gene expression in pathways known to be involved in vascular remodeling in the 5XFAD mice compared to Wt littermates, including pathways associated with angiogenesis and cardiovascular development. We also find that pharmacologic inhibition of PAI-1 in 5XFAD mice reduces abnormal vascular remodeling and improves cognition in the 5XFAD mice, without reducing plaque burden; and importantly that expression of genes within the vascular remodeling pathways are dramatically reduced in 5XFAD mice receiving the PAI-1 inhibitor. Based on the current literature and our preliminary data we will test the novel hypothesis that there is a causal relationship between vascular remodeling, and impaired cognition in the context AD, and that PAI-1 plays a critical role promoting pathologic vascular remodeling during AD development and progression.

抽象的 阿尔茨海默病 (AD) 的病理生理学非常复杂，是最困难和最复杂的疾病之一。 现代神经科学面临的紧迫挑战包括： 过度磷酸化的 tau 蛋白和由聚集的细胞外淀粉样蛋白 (Aβ) 组成的老年斑是 AD 的标志性病理特征 然而，很明显其他因素也可能导致神经损伤。 越来越多的临床和实验数据表明，系统故障和认知障碍与 AD 相关。 促进血管重塑和功能障碍的心血管疾病（CVD）危险因素是 与认知障碍有关，并且是 AD 痴呆发展的重要危险因素。 这些研究包括直接联系与血管损伤相关的途径的观察，例如 止血、血管生成和高血压对 AD 的影响，导致人们假设 CVD 危险因素可能通过 例如，目前的数据表明，促进 AD 发生或进展的常见机制。 斑块、缠结和 CVD 危险因素都会上调纤溶酶原激活剂抑制剂 1 (PAI-1) 的表达， 最近的研究还表明，PAI-1 可能是一种诊断生物标志物和/或 是临床 AD 的危险因素，PAI-1 表达随着年龄的增长而增加，是 AD 最重要的危险因素 PAI-1 在 AD 小鼠模型中的调节纤维蛋白溶解和伤口的作用最为人们所了解。 5XFAD 中提供的初步数据显示，PAI-1 缺乏与改善的结果相关。 在淀粉样蛋白生成小鼠模型中，我们发现显着的血管重塑与淀粉样蛋白同时发生 这些变化与皮质血减少有关。 流和增加的 PAI-1 表达和通路分析发现了显着的增加。 与 Wt 小鼠相比，5XFAD 小鼠中已知参与血管重塑的途径中的基因表达 同窝动物，包括与血管生成和心血管发育相关的途径。 5XFAD 小鼠中 PAI-1 的药理抑制可减少异常血管重塑并改善 5XFAD 小鼠的认知能力，而不减少斑块负担，重要的是，其中的基因表达； 接受 PAI-1 抑制剂的 5XFAD 小鼠的血管重塑途径显着减少。 根据当前的文献和我们的初步数据，我们将检验新的假设，即存在因果关系 AD 背景下血管重塑与认知受损之间的关系，并且 PAI-1 发挥着重要作用 在 AD 发生和进展过程中促进病理性血管重塑的关键作用。