Abstract
In multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, neurodegeneration is detected early in the disease course and is associated with the long-term disability of patients. Neurodegeneration is linked to both inflammation and demyelination, but its exact cause remains unknown. This gap in knowledge contributes to the current lack of treatments for the neurodegenerative phase of MS. Here we ask if neurodegeneration in MS affects specific neuronal components and if it is the result of demyelination. Neuropathological examination of secondary progressive MS motor cortices revealed a selective vulnerability of inhibitory interneurons in MS. The generation of a rodent model of focal subpial cortical demyelination reproduces this selective neurodegeneration providing a new preclinical model for the study of neuroprotective treatments.
Highlights
Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the human central nervous system (CNS) characterised by inflammation, focal areas of demyelination and neurodegeneration
We have identified a distinct neurodegenerative signature in the secondary progressive MS motor cortex characterized by the selective loss of interneuron subtypes and their connections
In a preclinical mouse model, we showed that this selective vulnerability is secondary to cortical demyelination and affects PV +, fast-spiking interneurons
Summary
Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the human central nervous system (CNS) characterised by inflammation, focal areas of demyelination and neurodegeneration. Current treatments that modulate this immune attack suppress the inflammatory demyelinating white matter lesions (as assessed by magnetic resonance imaging—MRI) and accompanying relapses, but fail to prevent neurodegeneration [16]. Long term disability better correlates with brain atrophy on MRI rather than with white matter demyelinating lesion load, but the mechanisms leading to these changes remain largely unknown [7, 8, 22]. This limited understanding may contribute to the lack of successful therapies counteracting neurodegeneration. Two fundamental questions need to be addressed: first, which neural components are primarily affected? Second, does neurodegeneration result directly from demyelination?
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