Differential effects of aging and Alzheimer's disease on microemboli clearance in a mouse model of microinfarction

Abstract

BackgroundCerebral microinfarcts often occur as a result of microvessel occlusion and are prevalent among dementia patients and the aging population. Detailed studies on the timecourse of microvascular occlusions indicate that endogenous mechanisms exist to re-canalize occluded vessels. One recently discovered mechanism is angiophagy, where vessels engulf and expel microemboli, thus mitigating damage caused by micro-occlusions. While several previous studies have shown that angiophagy occurs in rodent models, the frequency and timing of this process is not well characterized. In addition, there is limited data on the impact of aging on angiophagy, or the occurrence of this process in clinically relevant diseases such as Alzheimers disease. MethodsTo further study the timecourse of angiophagy, we induced micro-occlusions in young, aged and 3xTg Alzheimers mice via injection of 20m microspheres into the carotid artery. Mice were sacrificed on day 3, 7 or 14 and the brains were processed for brain-wide localization of microspheres and quantification of angiophagy. ResultsWe found the largest number of microspheres in the neocortex, yet when accounting for region size, microspheres were more evenly distributed across brain regions. When quantifying angiophagy in young non-diseased mice, we found that approximately 43% of microspheres had extravasated from the vessel by day 14. This process was delayed in aged mice, with only 10% of microspheres extravasated by day 14. Moreover, in young 3xTg Alzheimers mice, we found the rate of angiophagy to be more efficient at day 14 compared to non-transgenic controls, with 47% and 43% of microspheres extravasated, respectively. A similar trend was observed in aged Alzheimers mice, in which 38% of microspheres were extravasated by day 14 in 3xTg mice, compared to only 30% in non-transgenic controls. ConclusionsTaken together, we find that while aging impairs the process of angiophagy, Alzheimers mice exhibit a paradoxical increase in the rate of microsphere extravasation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/679680v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@760ec2org.highwire.dtl.DTLVardef@c2e2caorg.highwire.dtl.DTLVardef@b76011org.highwire.dtl.DTLVardef@1040eec_HPS_FORMAT_FIGEXP M_FIG C_FIG