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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




Journal article


J Neurosci

Publication Date





18185 - 18194


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