The unexpected dual role of S100A9 amyloid protein on neurodegeneration in progressive multiple sclerosis motor cortex

Motor cortical inflammation and neurodegeneration are key features of progressive multiple sclerosis (MS), contributing to irreversible motor disability. However, the precise mechanisms leading to neuronal loss remain poorly understood. While chronic inflammation is a hallmark of MS and contributes to disease progression, the factors linking inflammation to neuronal loss in the cortex are not well defined. One candidate is the calcium-binding protein S100A9, a damage-associated molecular pattern (DAMP) protein, thought to be released by stressed cells and infiltrating monocytes. Through its ability to modulate immune responses and influence neuronal survival, S100A9 may sustain chronic inflammation and participate in neurodegenerative processes. Although its role has been explored in other neurological disorders, its contribution to progressive MS remains largely uncharacterised. Here, we investigated S100A9 expression in the motor cortex of a large post-mortem cohort of MS cases (n=67) and controls (n=9), focusing on its cellular localisation and its relationship with neuronal density and vascular pathology. S100A9 expression was increased in progressive MS cases compared to controls, predominantly localised to intravascular monocytes and as amyloid-like extracellular plaques surrounding blood vessels. These patterns were associated with neurodegeneration and blood-brain barrier (BBB) disruption, as evidenced by correlations with reduced brain weight, decreased neuronal density, and increased fibrin(ogen) deposition. In contrast, S100A9 was also expressed in microglia, where it correlated with increased neuronal density and reduced fibrin(ogen) deposition. Notably, the phosphorylated form of S100A9, linked to pro-inflammatory signaling, was reduced in microglia but enriched in perivascular regions. These findings reveal a dual, compartment-specific role for S100A9 in progressive MS, whereby extracellular aggregates may drive neurotoxicity, while microglial S100A9 may confer neuroprotection. Therapeutic strategies targeting extracellular S100A9 while preserving its intracellular functions may offer new opportunities for treating progressive MS.