Microtubular proteolysis in focal cerebral ischemia

L. Creed Pettigrew, Mary L. Holtz, Susan D. Craddock, Stephen L. Minger, Nathan Hall, James W. Geddes

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

Calpain, a neutral protease activated by calcium, may promote microtubular proteolysis in ischemic brain. We tested this hypothesis in an animal model of focal cerebral ischemia without reperfusion. The earliest sign of tissue injury was observed after no more than 15 min of ischemia, with coiling of apical dendrites immunolabeled to show microtubule-associated protein 2 (MAP2). After 6 h of ischemia, MAP2 immunoreactivity was markedly diminished in the infarct zone. Quantitative Western analysis demonstrated that MAP2 was almost unmeasurable after 24 h of ischemia. An increase in calpain activity, shown by an antibody recognizing calpain-cleaved spectrin fragments, paralleled the loss of MAP2 immunostaining. Double labeled immunofluorescent studies showed that intraneuronal calpain activity preceded evidence of MAP2 proteolysis. Perikaryal immunolabeling of τ protein became increasingly prominent between 1 and 6 h in neurons located within the transition zone between ischemic and unaffected tissue. Western blot experiments confirmed that dephosphorylation of τ protein occurred during 24 h of ischemia, but was not associated with significant loss of τ antigen. We conclude that focal cerebral ischemia is associated with early microtubular proteolysis caused by calpain.

Original languageEnglish
Pages (from-to)1189-1202
Number of pages14
JournalJournal of Cerebral Blood Flow and Metabolism
Volume16
Issue number6
DOIs
StatePublished - 1996

Keywords

  • Calpain
  • Cerebral ischemia
  • Microtubule-associated proteins
  • Peptide hydrolases
  • Tau proteins

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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