Oxysterol Alterations in SOD1G93A ALS Rats: 25-Hydroxycholesterol and LPS-Binding Protein in Disease Progression

Lima, R. S.; Santos, R.; Chaves-Filho, A. B.; Trzan, I. F. L.; Inague, A.; Faria, R. L.; Dantas, L. S.; Pinto, I. F. D.; Medeiros, M. H. G.; Steiner, A. A.; Miyamoto, S.

doi:10.1101/2025.05.05.650333

bioRxiv · 10.1101/2025.05.05.650333

Oxysterol Alterations in SOD1G93A ALS Rats: 25-Hydroxycholesterol and LPS-Binding Protein in Disease Progression

Lima, R. S.·Santos, R.·Chaves-Filho, A. B.·Trzan, I. F. L.·Inague, A.·Faria, R. L.·Dantas, L. S.·Pinto, I. F. D.·Medeiros, M. H. G.·Steiner, A. A.·Miyamoto, S.

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Abstract

BackgroundDisruptions in cholesterol and oxysterol metabolism, along with neuroinflammation, are linked to amyotrophic lateral sclerosis (ALS), though the underlying mechanisms remain unclear. Given evidence of increased intestinal permeability in ALS, we investigated its link to neuroinflammation and oxysterol alterations in SOD1G93A rats. MethodsOxysterols were quantified in plasma and spinal cord from presymptomatic and symptomatic SOD1G93A rats and age-matched controls via ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry. Circulating LBP, a marker of intestinal permeability, was quantified via ELISA. ResultsOxysterols involved in bile acid biosynthesis - 7-hydroxycholesterol, 27-hydroxycholesterol (27-OH), and 3{beta}-hydroxycholestenoic acid - were increased in the plasma of symptomatic rats. The neuronal oxysterol 24(S)-hydroxycholesterol (24(S)-OH) decreased in the spinal cord but increased in the plasma. In contrast, 27-OH and 25-hydroxycholesterol (25-OH) levels were elevated in both plasma and spinal cord, with 25-OH rising during the presymptomatic stage. Presymptomatic animals also exhibited elevated LBP levels, which strongly correlated with spinal cord 25-OH levels, suggesting a link between systemic inflammation and neuroinflammation in ALS. ConclusionOxysterol alterations in plasma and spinal cord suggest compromised blood-spinal cord barrier integrity and early neuroinflammation. Elevated LBP levels indicate increased intestinal permeability and circulating LPS as contributors to neuroinflammation and neurodegeneration. These findings highlight 25-OH and LBP as markers and mediators of gut-brain axis interactions in ALS pathogenesis, particularly in the presymptomatic phase.

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Lima, R. S., Santos, R., Chaves-Filho, A. B., Trzan, I. F. L., Inague, A., Faria, R. L., Dantas, L. S., Pinto, I. F. D., Medeiros, M. H. G., Steiner, A. A., Miyamoto, S.. 2025-05-07. Oxysterol Alterations in SOD1G93A ALS Rats: 25-Hydroxycholesterol and LPS-Binding Protein in Disease Progression. https://doi.org/10.1101/2025.05.05.650333

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