Compromised axon initial segment integrity in EAE is preceded by microglial reactivity and contact
Kareem C Clark1,2, Anna Josephson1, Savannah D Benusa1,2
1Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia.
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.
Insights
Inflammation, not demyelination, disrupts the axon initial segment (AIS) in multiple sclerosis models. Therapeutic intervention with didox may reverse this critical axonal pathology.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Axonal pathology significantly contributes to long-term disability in multiple sclerosis (MS).
- The mechanisms driving axonal damage in MS, particularly concerning the axon initial segment (AIS), are not fully understood.
- Previous research indicated AIS integrity is compromised following demyelination.
Purpose of the Study:
- To investigate the mechanisms disrupting the axon initial segment (AIS) in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE), a model for MS.
- To determine whether demyelination or inflammation is the primary driver of AIS pathology.
- To evaluate the therapeutic potential of didox in mitigating AIS disruption.
Main Methods:
- Induction of experimental autoimmune encephalomyelitis (EAE) in mice to model MS.
- Administration of cuprizone to induce demyelination in control experiments.
- Assessment of AIS integrity using histological and imaging techniques.
- Evaluation of microglial reactivity and disease severity.
- Treatment of EAE mice with the drug didox.
Main Results:
- The axon initial segment (AIS) remained intact after cuprizone-induced demyelination.
- AIS integrity was significantly disrupted in the neocortex of EAE mice, independent of local demyelination.
- AIS pathology correlated with EAE clinical disease severity and duration, and with cortical microglial reactivity.
- Didox treatment attenuated AIS pathology and reduced microglial reactivity.
Conclusions:
- Inflammation, rather than demyelination, is the key factor disrupting AIS integrity in MS.
- AIS pathology is progressive and linked to disease severity in EAE.
- Therapeutic strategies targeting inflammation may protect against and reverse AIS pathology in MS.
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