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，是最困难和最困难的 现代神经科学面临的紧迫挑战。细胞内神经原纤维缠结(NFTs)包括 过度磷酸化的tau和由聚集的细胞外淀粉样β蛋白(Aβ)组成的老年斑是 阿尔茨海默病的病理特征。然而，很明显，其他因素可能对神经起作用。 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 促进血管重构和功能障碍的心血管疾病(CVD)危险因素 与认知障碍相关，是发展为阿尔茨海默病的重要危险因素。 这些研究包括观察与血管损伤相关的直接联系的通路，例如 止血、血管生成和高血压对阿尔茨海默病的影响，导致假设心血管危险因素可能通过 促进AD发展或进展的共同机制。例如，目前的数据显示， 斑块、缠结和心血管危险因素都上调纤溶酶原激活物抑制物1(PAI-1)的表达， 是一个独立的心血管疾病危险因素。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的表达随着年龄的增加而增加，这是AD的最重要的危险因素 痴呆症。PAI-1最为人所知的是其调节纤溶和创伤的作用，以及在AD小鼠模型中的作用 PAI-1缺乏与改善预后相关。在5XFAD中提供的初步数据中 在淀粉样变性小鼠模型中，我们发现显著的血管重塑与淀粉样蛋白同时发生 斑块形成和认知障碍。这些变化与皮质血的减少有关。 血流和PAI-1表达增加。RNA-Seq和通径分析发现， 与Wt相比，5XFAD小鼠中参与血管重塑的已知途径中的基因表达 包括与血管生成和心血管发育相关的通路。我们还发现 药物抑制5XFAD小鼠PAI-1减轻异常血管重塑并改善 在没有减少斑块负担的情况下，5XFAD小鼠的认知；重要的是，内部基因的表达 在接受PAI-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，我们将检验新的假设，即存在一个因果关系 血管重塑与阿尔茨海默病认知损害的关系及PAI-1的作用 促进病理性血管重塑在阿尔茨海默病发生发展中的关键作用。

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.