title: Rapid disruption of axon-glial integrity in response to mild cerebral hypoperfusion.
abstract: 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.
authors.affiliation: University of Edinburgh, Centre for Neuroregeneration, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Michell M
authors.initials: MM
authors.lastname: Reimer
authors.forename: Jamie
authors.initials: J
authors.lastname: McQueen
authors.forename: Luke
authors.initials: L
authors.lastname: Searcy
authors.forename: Gillian
authors.initials: G
authors.lastname: Scullion
authors.forename: Barbara
authors.initials: B
authors.lastname: Zonta
authors.forename: Anne
authors.initials: A
authors.lastname: Desmazieres
authors.forename: Philip R
authors.initials: PR
authors.lastname: Holland
authors.forename: Jessica
authors.initials: J
authors.lastname: Smith
authors.forename: Catherine
authors.initials: C
authors.lastname: Gliddon
authors.forename: Emma R
authors.initials: ER
authors.lastname: Wood
authors.forename: Pawel
authors.initials: P
authors.lastname: Herzyk
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brophy
authors.forename: James
authors.initials: J
authors.lastname: McCulloch
authors.forename: Karen
authors.initials: K
authors.lastname: Horsburgh
mesh_terms: D000367:Age Factors; D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D001369:Axons / Q000473:pathology*; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D002908:Chronic Disease; D003337:Corpus Callosum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D055032:Electron Microscope Tomography / Q000379:methods; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D004676:Myelin Basic Protein / Q000378:metabolism; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009413:Nerve Fibers, Myelinated / Q000378:metabolism; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000166:cytology / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D011901:Ranvier's Nodes / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D015222:Sodium Channels
chemical_list: C094681:Ank3 protein, mouse; D017487:Ankyrins; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; C491322:Cntnap1 protein, mouse; C104739:Mag protein, mouse; D004676:Myelin Basic Protein; D018992:Myelin-Associated Glycoprotein; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; C504593:Nfasc protein, mouse; C491046:Scn8a protein, mouse; D015222:Sodium Channels; C051774:neurofilament protein H