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

摘要 阿尔茨海默病（AD）的病理生理学是复杂的，并且代表了最困难和最困难的疾病之一。 现代神经科学面临的紧迫挑战细胞内神经元缠结（NFT），包括 过度磷酸化的tau蛋白和由聚集的细胞外淀粉样蛋白β（Aβ）组成的老年斑是 AD的标志性病理特征。然而，很明显，其他因素可能有助于神经 与AD相关的系统故障和认知障碍。越来越多的临床和实验数据表明， 促进血管重塑和功能障碍的心血管疾病（CVD）危险因素是 与认知障碍相关，并且是AD痴呆发展的重要风险因素。 这些研究包括直接联系与血管损伤相关的途径的观察结果， 止血、血管生成和高血压与AD的关系，导致假设CVD危险因素可能通过以下途径起作用： 促进AD发展或进展的共同机制。例如，目前的数据显示， 斑块、缠结和CVD危险因素均上调纤溶酶原激活物抑制剂1（派-1）的表达， 一个独立的CVD风险因素。最近的研究还表明，派-1可能是诊断生物标志物和/或 临床AD的危险因素，派-1表达随年龄增加而增加，是AD最重要的危险因素 痴呆派-1在调节纤维蛋白溶解和创伤中的作用，以及在AD小鼠模型中的作用， 派-1缺陷与改善的结果相关。在5XFAD中提供的初步数据中， 在淀粉样蛋白生成小鼠模型中，我们发现显著的血管重塑与淀粉样蛋白同时发生， 斑块发展和认知障碍。这些变化与皮质血液减少有关 流动和派-1表达增加。RNA-Seq和途径分析鉴定了在细胞内的 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 包括与血管生成和心血管发育相关的途径。我们还发现 在5XFAD小鼠中，派-1的药理学抑制减少了异常的血管重塑，并改善了 在5XFAD小鼠中的认知，而不减少斑块负荷;重要的是， 在接受派-1抑制剂的5XFAD小鼠中血管重塑途径显著减少。 基于目前的文献和我们的初步数据，我们将测试新的假设，有一个因果关系， 血管重塑和认知障碍之间的关系，派-1在AD中起着重要作用。 在AD的发生和发展过程中促进病理性血管重塑的关键作用。

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.