Novel regulation of vascular dementia

摘要 血管性痴呆（VaD）是痴呆的第二大常见原因，通常会引发进行性痴呆。 认知障碍类似于阿尔茨海默病（AD）。目前的治疗策略侧重于 AD和痴呆的局部病变没有导致令人满意的结果。因此，全面 迫切需要了解VaD和AD的发病机制，以解决未满足的科学和临床需求。 需求所有血管系统的血管病理也与VaD和AD相关。最值得注意的是， 动脉粥样硬化、中风和高血压加速了认知障碍和老年痴呆症的进展。 所有的原因。多项大型全基因组研究确定了动脉粥样硬化风险基因载脂蛋白E（APOE） 作为AD的一个强遗传风险因素。然而，尽管有共同的遗传风险因素，动脉粥样硬化和AD是 在临床管理和机制研究中经常分离。泛血管性疾病， 冠状动脉疾病、缺血性中风、动脉瘤和外周动脉疾病都与VaD相关， 因此，研究影响认知功能的泛血管变化可能会开辟新的途径， 了解AD和AD。目前的应用代表了我们揭示新机制的长期目标 将心血管和脑血管系统中的血管功能障碍与VaD和AD联系起来。我们的努力 发现Runt相关转录因子2（Runx 2）在调节主动脉和大脑中的新作用 血管病变和认知功能。我们和其他人之前报道过Runx 2是一个积分 血管钙化的调节器。我们的初步研究确定了Runx 2在调节 动脉粥样硬化，动脉硬化，脑血流量和小鼠的认知功能; Runx 2在衰老、动脉粥样硬化和AD小鼠以及人AD/VaD组织中的表达。单细胞RNA 测序分析进一步发现了Runx 2对SMC表型转换的新调控，超出了已知的 促进SMC钙化的活性。与一系列的分子，生物化学，蛋白质组学和生物信息学 初步研究揭示了Runx 2与一种重要的收缩SMC调节因子血清 响应因子（SRF），支持SMC表型转换中的新型Runx 2/SRF调控网络， 钙化阐明Runx 2和Runx 2依赖性信号转导在调节VaD中的新功能将 提供新的见解，以填补知识空白，这可能导致新的战略，临床管理或 治疗AD和AD。

Abstract Vascular dementia (VaD) is the second most common cause of dementia, often triggers progressive cognitive impairment similar to that of Alzheimer’s disease (AD). The current treatment strategies focusing on local lesions for AD and dementia have not led to satisfactory outcomes. Therefore, comprehensively understanding of the pathogenesis of VaD and AD is urgently required to address the unmet scientific and clinical needs. Vascular pathologies across all vasculature have also been linked to VaD and AD. Most notably, atherosclerosis, stroke and hypertension accelerate the progression of cognitive impairments and dementia of all causes. Multiple large genome-wide studies identify the atherosclerosis risk gene apolipoprotein E (APOE) as a strong genetic risk factor for AD. However, despite shared genetic risk factors, atherosclerosis and AD are often separated in clinical management and mechanistic studies. Pan-vascular diseases represented by coronary artery disease, ischemic stroke, aneurysm and peripheral artery disease are all associated with VaD, thus, investigating pan-vascular changes that impact cognitive functions may open up new avenues to understand VaD and AD. The current application represents our long-term goals to uncover novel mechanisms linking vascular dysfunctions in the cardio and cerebrovascular systems to VaD and AD. Our effort has led to the discovery of a new role of the Runt-related transcription factor 2 (Runx2) in regulating both aortic and cerebral vascular pathologies and cognitive functions. We and others previously reported that Runx2 is an integral regulator for vascular calcification. Our preliminary studies identified novel function of Runx2 in regulating atherosclerosis, arterial stiffness, cerebral blood flow and cognitive function in mice; and uncovered upregulation of Runx2 in aging, atherosclerosis and AD mice as well as in human AD/VaD tissues. Single cell RNA sequencing analysis further discovered a novel regulation of Runx2 on SMC phenotypic switch, beyond its known activity in promoting SMC calcification. With an array of molecular, biochemical, proteomics and bioinformatics approaches, preliminary studies uncovered Runx2 interaction with an essential contractile SMC regulator, serum response factor (SRF), supporting a novel Runx2/SRF regulatory network in SMC phenotypic switch and calcification. Elucidating the novel function of Runx2 and Runx2-dependent signaling in regulating VaD will provide new insights to fill the knowledge gaps, which may lead to novel strategies for clinical management or treatment of VaD and AD.