Liquefaction of the Brain Following Stroke Shares Multiple Characteristics with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism

Abstract

The response to ischemic injury in the brain is different to the response to ischemic injury in other organs and tissues. Almost exclusive to the brain, and for unknown reasons, dead tissue liquefies in response to ischemia by the process of liquefactive necrosis. However, the data we present here indicate that at the macroscopic, microscopic, and molecular level, liquefactive necrosis strongly resembles atherosclerosis. We show that chronic stroke infarcts contain foamy macrophages, cholesterol crystals, high levels of osteopontin and matrix metalloproteases, and a similar cytokine profile to atherosclerosis. Crystalline cholesterol is a principal driver of atherosclerosis, and because cholesterol is an important structural component of myelin, we propose that liquefactive necrosis in response to stroke is caused by an inflammatory response to myelin debris, and is exacerbated by the formation of cholesterol crystals within macrophages. We propose that this leads to the chronic production of high levels of proteases, which in a partially osteopontin-dependent mechanism, causes secondary neurodegeneration and encephalomalacia of the surrounding tissue. In support of this, we show that genetically ablating osteopontin substantially reduces the production of degradative enzymes following stroke, reduces secondary neurodegeneration, and improves recovery. These findings suggest that treatments that prevent or target the regression of atherosclerosis may also be useful for mitigating the harmful effects of liquefactive necrosis following stroke.