Liquefaction of the Brain following Stroke Shares a Similar Molecular and Morphological Profile with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism

Amanda G. Chung, Jennifer B. Frye, Jacob C. Zbesko, Eleni Constantopoulos, Megan Hayes, Anna G. Figueroa, Danielle A. Becktel, W. Antony Day, John Konhilas, Brian S Mckay, Thuy Vi V. Nguyen, Kristian Doyle

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
JournaleNeuro
Volume5
Issue number5
DOIs
StatePublished - Sep 1 2018

Fingerprint

Osteopontin
Atherosclerosis
Stroke
Brain
Brain Ischemia
Ischemia
Cholesterol
Matrix Metalloproteinases
Inflammation
Recovery of Function
Phagocytes
Myelin Sheath
Cell Nucleus
Proteins
Necrosis
Lipids
Enzymes

Keywords

  • cholesterol crystals
  • chronic infarct
  • liquefactive necrosis
  • matrix metalloproteinase
  • osteopontin
  • stroke

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Liquefaction of the Brain following Stroke Shares a Similar Molecular and Morphological Profile with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism. / Chung, Amanda G.; Frye, Jennifer B.; Zbesko, Jacob C.; Constantopoulos, Eleni; Hayes, Megan; Figueroa, Anna G.; Becktel, Danielle A.; Antony Day, W.; Konhilas, John; Mckay, Brian S; Nguyen, Thuy Vi V.; Doyle, Kristian.

In: eNeuro, Vol. 5, No. 5, 01.09.2018.

Research output: Contribution to journalArticle

Chung, Amanda G. ; Frye, Jennifer B. ; Zbesko, Jacob C. ; Constantopoulos, Eleni ; Hayes, Megan ; Figueroa, Anna G. ; Becktel, Danielle A. ; Antony Day, W. ; Konhilas, John ; Mckay, Brian S ; Nguyen, Thuy Vi V. ; Doyle, Kristian. / Liquefaction of the Brain following Stroke Shares a Similar Molecular and Morphological Profile with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism. In: eNeuro. 2018 ; Vol. 5, No. 5.
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AU - Frye, Jennifer B.

AU - Zbesko, Jacob C.

AU - Constantopoulos, Eleni

AU - Hayes, Megan

AU - Figueroa, Anna G.

AU - Becktel, Danielle A.

AU - Antony Day, W.

AU - Konhilas, John

AU - Mckay, Brian S

AU - Nguyen, Thuy Vi V.

AU - Doyle, Kristian

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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.

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