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Glia. 2016 Jul;64(7):1190-209. doi: 10.1002/glia.22991. Epub 2016 Apr 21.

Compromised axon initial segment integrity in EAE is preceded by microglial reactivity and contact.

Author information

1
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia.
2
VCU, Neuroscience Curriculum, Richmond, Virginia.
3
Department of Research,, Hunter Holmes McGuire VA Medical Center, Richmond, Virginia.
4
Molecules for Health, Inc, Richmond, Virginia.
5
Department of Neurology, VCU, Richmond, Virginia.
6
UPMC/Univ Paris 06 UMR S 1127, Institut Du Cerveau Et De La Moelle Épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, Paris, F-75013, France.
7
AP-HP, Hôpital De La Pitié Salpêtrière, Paris, F-75013, France.

Abstract

Axonal pathology is a key contributor to long-term disability in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), but the mechanisms that underlie axonal pathology in MS remain elusive. Evidence suggests that axonal pathology is a direct consequence of demyelination, as we and others have shown that the node of Ranvier disassembles following loss of myelin. In contrast to the node of Ranvier, we now show that the axon initial segment (AIS), the axonal domain responsible for action potential initiation, remains intact following cuprizone-induced cortical demyelination. Instead, we find that the AIS is disrupted in the neocortex of mice that develop experimental autoimmune encephalomyelitis (EAE) independent of local demyelination. EAE-induced mice demonstrate profound compromise of AIS integrity with a progressive disruption that corresponds to EAE clinical disease severity and duration, in addition to cortical microglial reactivity. Furthermore, treatment with the drug didox results in attenuation of AIS pathology concomitantly with microglial reversion to a less reactive state. Together, our findings suggest that inflammation, but not demyelination, disrupts AIS integrity and that therapeutic intervention may protect and reverse this pathology. GLIA 2016;64:1190-1209.

KEYWORDS:

axonal domain; axonal pathology; demyelination; inflammation; multiple sclerosis

PMID:
27100937
DOI:
10.1002/glia.22991
[Indexed for MEDLINE]

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