Novel regulation of vascular dementia

摘要 血管性痴呆(Vad)是导致痴呆症的第二大常见原因，通常会引发进行性痴呆。 类似于阿尔茨海默病(AD)的认知障碍。当前的治疗策略主要集中在 AD和痴呆症的局部损害并没有带来令人满意的结果。因此，全面 迫切需要了解VaD和AD的发病机制，以解决科学和临床上尚未解决的问题 需要。所有血管系统的血管病变也与VAD和AD有关。最值得注意的是， 动脉粥样硬化、中风和高血压加速认知障碍和痴呆的进展 所有原因。多项大型全基因组研究确定动脉粥样硬化危险基因载脂蛋白E(APOE) 是阿尔茨海默病的强烈遗传风险因素。然而，尽管有共同的遗传风险因素，动脉粥样硬化和阿尔茨海默病 在临床管理和机制研究中往往是分开的。泛血管疾病的代表是 冠状动脉疾病、缺血性中风、动脉瘤和外周动脉疾病都与VaD有关， 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VAD和AD。目前的应用代表了我们发现新机制的长期目标 将心脑血管系统的血管功能障碍与VaD和AD联系起来。我们的努力导致了 Run-Related转录因子2(Runx2)在调节主动脉和脑中的新作用的发现 血管病理和认知功能。我们和其他人之前曾报道，Runx2是一个完整的 血管钙化调节剂。我们的初步研究确定了Runx2在调节中的新功能 小鼠的动脉粥样硬化、动脉僵硬、脑血流和认知功能；以及未发现的上调 Runx2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Runx2对SMC表型开关的一种新的调节，这超出了它的已知范围 促进SMC钙化的活性。拥有一系列的分子、生化、蛋白质组学和生物信息学 方法：初步研究发现Runx2与一种重要的SMC收缩调节因子血清相互作用 响应因子(SRF)，支持SMC表型交换机中的新型Runx2/SRF调节网络 钙化。Runx2及其依赖的信号通路在调节VaD意志中的新功能 提供新的见解来填补知识空白，这可能会导致临床管理或 VaD和AD的治疗。

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.