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成因素 血管性认知损害和痴呆(VCID)的因素。人们越来越普遍地认为，血管质量差 健康促进大脑健康不良，需要改变以延迟或预防VCID的发病。 动脉粥样硬化性血管疾病(AVD)是一种慢性、不适应的炎症性疾病，可影响外部和外部 颅内动脉。脂蛋白滞留，内皮细胞炎症， 单核/巨噬细胞浸润，细胞内胆固醇积聚，细胞凋亡清除受损，以及 细胞外基质降解导致晚期不稳定动脉粥样硬化斑块的形成 或阻断流向组织的血液，造成急性或慢性组织损伤。ICAS通常在以下方面发挥因果作用 缺血性中风和随后的认知能力下降。ICAS也被认为与认知能力的临床症状 衰弱与阿尔茨海默病的病理。与颅外动脉粥样硬化相比，颅内动脉粥样硬化有延迟 发病年龄约为20岁，但在60岁或以上的人中患病率和严重性有所增加。有了稳定的 随着美国60岁以上公民比例的上升，ICAS在发病率中将发挥越来越大的作用 以及由VCID引起的死亡。使用他汀类药物降低低密度脂蛋白(LDL)浓度是主要的 稳定AVD和降低缺血性中风风险的治疗方法。然而，他汀类药物只能减少中风 风险降低约20%，而且似乎不能减少VCID，这表明单独治疗高胆固醇血症并不是 减少VCID的理想方法。显然需要更多的治疗方法来消退或稳定ICAS 由于缺乏合适的动物模型而受到阻碍。在一项由R01资助的研究期间，以确定 关于microRNA-33(miR-33)对心血管AVD的拮抗作用，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 可能对VCID研究领域产生很大影响，因为可能会发现一种 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.