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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 publication

DOI

10.1523/JNEUROSCI.4936-11.2011

Type

Journal article

Journal

J Neurosci

Publication Date

07/12/2011

Volume

31

Pages

18185 - 18194

Keywords

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 Protein, Myelin-Associated Glycoprotein, NAV1.6 Voltage-Gated Sodium Channel, 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