Targeting microRNA-33 to reduce intracranial atherosclerosis and other neurovascular hallmarks of vascular cognitive impairment and dementia

项目摘要 颅内动脉粥样硬化（ICAS）是一个公共卫生问题，因为它在中风中的作用和作为一个促进动脉粥样硬化的因素， 血管性认知功能障碍和痴呆（VCID）。人们越来越普遍地认为， 健康促进大脑健康不良，需要改变以延迟或预防VCID的发作。 动脉粥样硬化性血管病（AVD）是一种慢性、适应不良的炎症性疾病，可影响血管外和 颅内动脉脂蛋白滞留，内皮细胞炎症， 单核细胞/巨噬细胞浸润、细胞内胆固醇蓄积、凋亡细胞清除受损，以及 细胞外基质降解导致晚期不稳定的动脉粥样硬化斑块的形成， 或阻塞流向组织的血流，引起急性或慢性组织损伤。ICAS通常在以下方面起着致病作用： 缺血性中风和随后认知能力下降。ICAS还与认知功能障碍的临床体征 和阿尔茨海默病病理学的关系。颅内动脉粥样硬化与颅外动脉粥样硬化相比， 发病约20年，但在60岁或以上的个体中患病率和严重程度增加。稳步 随着60岁以上美国公民比例的上升，ICAS将在发病率方面发挥越来越大的作用。 和VCID引起的死亡率。降低低密度脂蛋白（LDL）浓度与他汀类药物是主要的 稳定AVD和降低缺血性卒中风险的治疗方法。然而，他汀类药物只能减少中风 风险降低约20%，并且似乎没有降低VCID，这表明单独治疗高胆固醇血症不是一种有效的方法。 降低VCID的理想方法。对使ICAS消退或稳定的额外疗法的明显需求已经 但由于缺乏合适的动物模型而受到阻碍。在一项由R 01资助的研究中， microRNA-33（miR-33）拮抗心血管AVD的研究中，我们偶然发现我们的NHP模型 有ICAS和其他VCID的神经血管特征。我们相信对颅内动脉和大脑的分析 来自我们的NHP可能对VCID研究领域产生很大影响，因为可能发现 VCID的新疗法和动物模型。

Project Summary Intracranial atherosclerosis (ICAS) is a public health concern for both its role in stroke and as a contributing factor to vascular cognitive impairment and dementia (VCID). It is becoming widely accepted that poor vascular health facilitates poor brain health and that changes are needed to delay or prevent onset of VCID. Atherosclerotic vascular disease (AVD) is a chronic, maladaptive inflammatory disease that can affect extra- and intracranial arteries. The combination of lipoprotein retention, endothelial cell inflammation, monocyte/macrophage infiltration, intracellular cholesterol accumulation, impaired apoptotic cell clearance, and extracellular matrix degradation leads to formation of advanced, unstable atherosclerotic plaques that can limit or occlude blood flow to tissues causing acute or chronic tissue damage. ICAS often plays a causative role in ischemic stroke and subsequent cognitive decline. ICAS has also been linked to both clinical signs of cognitive decline and Alzheimer's disease pathology. Intracranial compared to extracranial atherosclerosis has a delayed onset of ~20 years but increases in prevalence and severity in individuals 60 years or older. With the steady rise in the percentage of US citizens above the age of 60, ICAS will play an ever-growing role in the morbidity and mortality caused by VCID. Reducing low-density lipoprotein (LDL) concentration with statins is a primary therapeutic approach to stabilize AVD and attenuate ischemic stroke risk. However, statins only reduce stroke risk by ~20% and do not appear to reduce VCID suggesting that treating hypercholesterolemia alone is not an ideal approach for reducing VCID. The obvious need for additional therapies that regress or stabilize ICAS has been hampered by the paucity of suitable animal models. During an R01-funded study to determine the impact of microRNA-33 (miR-33) antagonism on cardiovascular AVD, we fortuitously discovered that our NHP model had ICAS and other neurovascular hallmarks of VCID. We believe analysis of intracranial arteries and brains from our NHPs could have a high impact on the field of VCID research because of the potential discovery of a new therapy and animal model for VCID.