Persistent activation of microglia is associated with neuronal dysfunction of callosal projecting pathways and...

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Multiple sclerosis (MS) is characterized by cortical pathology, callosal atrophy, and axonal loss, contributing to disease progression.
• Existing models often focus on T-cell infiltrates during acute phases, potentially overlooking chronic mechanisms.

Purpose of the Study:

• To investigate cortical and callosal neuropathology in a mouse model of relapsing-remitting MS.
• To explore the role of microglia activation in chronic disease progression and its correlation with neuronal damage.

Main Methods:

• Utilized the relapsing-remitting experimental autoimmune encephalomyelitis (EAE) model in SJL mice.
• Examined cortical, periventricular subcortical lesions, and callosal demyelination.
• Assessed microglia activation, neurofilament phosphorylation, synaptic protein levels, and neuronal/axonal labeling.

Main Results:

• Identified cortical lesions, periventricular subcortical lesions, and callosal demyelination mirroring MS pathology.
• Demonstrated persistent microglia activation throughout the chronic disease phase, unlike transient T-cell infiltrates.
• Correlated microglia activation with abnormal neurofilament phosphorylation and synaptic protein loss in projecting neurons.
• Observed impaired retrograde labeling of neurons and reduced labeling of their axons.

Conclusions:

• Established a novel paradigm of cortical and callosal neuropathology in an MS mouse model, driven by innate immunity.
• The findings closely mimic human MS pathology, particularly periventricular and cortical lesions.
• This model provides a valuable tool for studying the mechanisms underlying MS progression.