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

2025 · doi:10.1101/2025.05.05.650333
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This study examined oxysterol and cholesterol pathway changes and gut–brain inflammatory indicators in presymptomatic versus symptomatic SOD1G93A rat models of amyotrophic lateral sclerosis, quantifying multiple oxysterols in plasma and spinal cord by UHPLC–HRMS and measuring circulating lipopolysaccharide-binding protein (LBP) by ELISA. The authors found that bile-acid–related oxysterols (7α-hydroxycholesterol, 27-hydroxycholesterol, and 3β-hydroxycholestenoic acid) increased in symptomatic plasma, while spinal 24(S)-hydroxycholesterol decreased and plasma 24(S)-hydroxycholesterol increased. Notably, 27-hydroxycholesterol and 25-hydroxycholesterol were elevated in both plasma and spinal cord, with 25-hydroxycholesterol rising already during the presymptomatic stage, and presymptomatic animals showed elevated LBP that strongly correlated with spinal cord 25-hydroxycholesterol. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Background Disruptions 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.

Methods

Oxysterols 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.

Results

Oxysterols involved in bile acid biosynthesis - 7α-hydroxycholesterol, 27-hydroxycholesterol (27-OH), and 3β-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.

Conclusion

Oxysterol 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. Competing Interest Statement The authors have declared no competing interest.

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