Glycosylation of Human Plasma Clusterin Yields a Novel Candidate Biomarker of Alzheimer鈥檚 Disease

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• 作者：Hui-Chung Liang ; Claire Russell ; Vikram Mitra ; Raymond Chung ; Abdul Hye ; Chantal Bazenet ; Simon Lovestone ; Ian Pike ; Malcolm Ward
• 刊名：Journal of Proteome Research
• 出版年：2015
• 出版时间：December 4, 2015
• 年：2015
• 卷：14
• 期：12
• 页码：5063-5076
• 全文大小：665K
• ISSN：1535-3907

文摘

Specific glycosylated peptides of clusterin are found associated with hippocampal atrophy. The glycosylation of clusterin from human plasma was comprehensively analyzed and characterized using mass spectrometry (MS)-based glycoproteomics analysis. All six known N-glycosylation sites are covered, three in the alpha subunit (伪64N, 伪81N and 伪123N) and three in the beta subunit (尾64N, 尾127N, and 尾147N). More detailed structural characterization of clusterin glycopeptides was also performed, demonstrating the presence of glycosylated peptides and their corresponding glycans. Using liquid chromatography鈥搕andem mass spectrometry (LC鈥揗S/MS), we have determined the differences in the glycoforms associated at each of the different glycosylation sites in plasma clusterin obtained from subjects of low hippocampal atrophy (n = 13) and high hippocampal atrophy (n = 14). In our pilot study, the 尾64N site shows the most significant regulations between clinical groups. Eight 尾64N glycoforms are significantly reduced in patients with high atrophy compared with those with low atrophy, which demonstrates the utility of clusterin isoforms as diagnostic and prognostic Alzheimer鈥檚 disease (AD) markers. These results provide a novel and robust workflow suitable for rapid verification of specific clusterin glycoforms with utility as AD biomarkers.