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<p>Chondroitin sulfate (CS) is an essential sulfated glycan in the brain, but standard LC-MS/MS disaccharide analysis provides only limited quantitative accuracy for detecting CS structural changes under physiological and pathophysiological conditions. Here, we incorporated eight distinct <sup>13</sup>C-labeled CS disaccharide calibrants into the analytical workflow. Using this enhanced approach, we identified structural alterations in both sulfation patterns and total CS abundance in pre-clinical and clinical Alzheimer’s disease (AD) brain samples compared with controls. Analysis of cerebrospinal fluid (CSF) from AD patients further revealed elevated levels of the <b>CS-E</b> disaccharide and reduced levels of hyaluronic acid. Functionally, we found that synthetic CS-E 19-mer—but not other synthetic CS 19-mer subtypes—impaired neuronal growth, underscoring the need to pinpoint specific CS structures that contribute to neurodegeneration. Because CS abnormalities are detectable in the pre-clinical AD brain, our findings raise the possibility that CS glycans could serve as early biomarkers for AD.</p>

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Quantitative LC-MS/MS profiling reveals aberrant chondroitin sulfate in Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月28日

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  • Yongmei Xu,
  • Haoran Wang,
  • Zhangjie Wang,
  • Jianxiang Zhang,
  • Eduardo Stancanelli,
  • Qin Xu,
  • Yiru Hou,
  • Chunyu Wang,
  • Peng Zhang,
  • Marla Gearing,
  • Jian Liu

摘要

Chondroitin sulfate (CS) is an essential sulfated glycan in the brain, but standard LC-MS/MS disaccharide analysis provides only limited quantitative accuracy for detecting CS structural changes under physiological and pathophysiological conditions. Here, we incorporated eight distinct 13C-labeled CS disaccharide calibrants into the analytical workflow. Using this enhanced approach, we identified structural alterations in both sulfation patterns and total CS abundance in pre-clinical and clinical Alzheimer’s disease (AD) brain samples compared with controls. Analysis of cerebrospinal fluid (CSF) from AD patients further revealed elevated levels of the CS-E disaccharide and reduced levels of hyaluronic acid. Functionally, we found that synthetic CS-E 19-mer—but not other synthetic CS 19-mer subtypes—impaired neuronal growth, underscoring the need to pinpoint specific CS structures that contribute to neurodegeneration. Because CS abnormalities are detectable in the pre-clinical AD brain, our findings raise the possibility that CS glycans could serve as early biomarkers for AD.