RT Journal Article
SR Electronic
T1 Liquefaction of the Brain following Stroke Shares a Similar Molecular and Morphological Profile with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0076-18.2018
DO 10.1523/ENEURO.0076-18.2018
VO 5
IS 5
A1 Amanda G. Chung
A1 Jennifer B. Frye
A1 Jacob C. Zbesko
A1 Eleni Constantopoulos
A1 Megan Hayes
A1 Anna G. Figueroa
A1 Danielle A. Becktel
A1 W. Antony Day
A1 John P. Konhilas
A1 Brian S. McKay
A1 Thuy-Vi V. Nguyen
A1 Kristian P. Doyle
YR 2018
UL http://www.eneuro.org/content/5/5/ENEURO.0076-18.2018.abstract
AB Here we used mouse models of heart and brain ischemia to compare the inflammatory response to ischemia in the heart, a protein rich organ, to the inflammatory response to ischemia in the brain, a lipid rich organ. We report that ischemia-induced inflammation resolves between one and four weeks in the heart compared to between eight and 24 weeks in the brain. Importantly, we discovered that a second burst of inflammation occurs in the brain between four and eight weeks following ischemia, which coincided with the appearance of cholesterol crystals within the infarct. This second wave shares a similar cellular and molecular profile with atherosclerosis and is characterized by high levels of osteopontin (OPN) and matrix metalloproteinases (MMPs). In order to test the role of OPN in areas of liquefactive necrosis, OPN-/- mice were subjected to brain ischemia. We found that at seven weeks following stroke, the expression of pro-inflammatory proteins and MMPs was profoundly reduced in the infarct of the OPN-/- mice, although the number of cholesterol crystals was increased. OPN-/- mice exhibited faster recovery of motor function and a higher number of neuronal nuclei (NeuN) positive cells in the peri-infarct area at seven weeks following stroke. Based on these findings we propose that the brain liquefies after stroke because phagocytic cells in the infarct are unable to efficiently clear cholesterol rich myelin debris, and that this leads to the perpetuation of an OPN-dependent inflammatory response characterized by high levels of degradative enzymes.