Evaluating Microemboli Clearance in a Mouse Model of Microinfarction

Abstract

Cerebral microinfarcts, ranging from 100μm to 3mm in diameter, occur as a result of ischemic microvessel occlusion. Microinfarcts have been found to contribute to cognitive decline and are particularly prevalent in dementia patients and the aging population. Microemboli occlusions are primarily cleared via fibrinolysis and hemodynamic forces to re-establish blood flow. Angiophagy, where vessels engulf and expel microemboli, may also mitigate damage caused by micro-occlusions. Previous rodent studies have proposed conflicting timelines on the extent to which this process occurs and fail to extensively quantify angiophagy in clinically relevant populations, including aging and Alzheimer's disease. To further study this process of angiophagy, we induced micro-occlusions in young, aged and AD mice via injection of 20μm microspheres into the carotid artery. In characterizing this model, we found that most microspheres localized to the cortex, yet when accounting for region size, microspheres were more evenly distributed across regions. When quantifying angiophagy in young non-diseased mice, we found that approximately 43% of microspheres have extravasated from the vessel by day 14. This timeline was delayed in aged mice, with only 10% of microspheres extravasated by day 14. Moreover, in young 3xTg Alzheimer's mice, we find the rate of angiophagy is more efficient at day 14 compared to non-transgenic controls, with 47% and 43% of microspheres extravasated, respectively. A similar trend is observed in aged Alzheimer's mice whereby 38% of microspheres extravasated by day 14 in 3xTg mice, compared to only 30% in non-transgenic controls. Taken together, we show that aging impairs the process of angiophagy, while Alzheimer's mice exhibit an increased ability to extravasate microspheres.