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

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.