Rapid Disruption of Axon–Glial Integrity in Response to Mild Cerebral Hypoperfusion

Michell M Reimer, Jamie Mcqueen, Luke Searcy, Gillian Scullion, Barbara Zonta, Anne Desmazieres, Philip R Holland, Jessica Smith, Catherine Gliddon, Emma R Wood, Pawel Herzyk, Peter J Brophy, James McCulloch, Karen Horsburgh

Research output: Contribution to journalArticlepeer-review


Myelinated axons have a distinct protein architecture essential for action potential propagation, neuronal communication, and maintaining cognitive function. Damage to myelinated axons, associated with cerebral hypoperfusion, contributes to age-related cognitive decline. We sought to determine early alterations in the protein architecture of myelinated axons and potential mechanisms after hypoperfusion. Using a mouse model of hypoperfusion, we assessed changes in proteins critical to the maintenance of paranodes, nodes of Ranvier, axon-glial integrity, axons, and myelin by confocal laser scanning microscopy. As early as 3 d after hypoperfusion, the paranodal septate-like junctions were damaged. This was marked by a progressive reduction of paranodal Neurofascin signal and a loss of septate-like junctions. Concurrent with paranodal disruption, there was a significant increase in nodal length, identified by Nav1.6 staining, with hypoperfusion. Disruption of axon-glial integrity was also determined after hypoperfusion by changes in the spatial distribution of myelin-associated glycoprotein staining. These nodal/paranodal changes were more pronounced after 1 month of hypoperfusion. In contrast, the nodal anchoring proteins AnkyrinG and Neurofascin 186 were unchanged and there were no overt changes in axonal and myelin integrity with hypoperfusion. A microarray analysis of white matter samples indicated that there were significant alterations in 129 genes. Subsequent analysis indicated alterations in biological pathways, including inflammatory responses, cytokine-cytokine receptor interactions, blood vessel development, and cell proliferation processes. Our results demonstrate that hypoperfusion leads to a rapid disruption of key proteins critical to the stability of the axon-glial connection that is mediated by a diversity of molecular events.
Original languageEnglish
Pages (from-to)18185-18194
Number of pages10
JournalThe Journal of Neuroscience
Issue number49
Publication statusPublished - Dec 2011


  • Age Factors
  • Animals
  • Ankyrins
  • Axons
  • Cell Adhesion Molecules
  • Cell Adhesion Molecules, Neuronal
  • Chronic Disease
  • Corpus Callosum
  • Disease Models, Animal
  • Electron Microscope Tomography
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Hypoxia-Ischemia, Brain
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Myelin Basic Proteins
  • Myelin-Associated Glycoprotein
  • Nerve Fibers, Myelinated
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Neurofilament Proteins
  • Neuroglia
  • Neurons
  • Oligonucleotide Array Sequence Analysis
  • Optic Nerve
  • Ranvier's Nodes
  • Signal Transduction
  • Sodium Channels


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