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

项目总结

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.