Glycan biomarkers for Alzheimer disease correlate with T‐tau and P‐tau in cerebrospinal fluid in subjective cognitive impairment

• Published in: The FEBS journal 2020-08, Vol.287 (15), p.3221-3234
• Main Authors: Schedin‐Weiss, Sophia, Gaunitz, Stefan, Sui, Ping, Chen, Qiushi, Haslam, Stuart M., Blennow, Kaj, Winblad, Bengt, Dell, Anne, Tjernberg, Lars O.
• Format: Article
• Language: English
• Subjects: aberrant glycosylation; Aged; Aged, 80 and over; Alzheimer disease; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - diagnosis; Alzheimer's disease; Binding; Biochemistry & Molecular Biology; Biomarkers; Biomarkers - cerebrospinal fluid; Biomarkers - metabolism; Case-Control Studies; Cerebrospinal fluid; Clinical Medicine; Cognitive ability; Cognitive Dysfunction - cerebrospinal fluid; Cognitive Dysfunction - diagnosis; Correlation; csf; Dementia disorders; diagnosis; Disease Progression; Female; Global health; Glycan; Glycomics; Glycosylation; Humans; Impairment; Ionization; Klinisk medicin; Liquid chromatography; Male; Mass spectrometry; Mass spectroscopy; Medical treatment; Medicin och hälsovetenskap; Middle Aged; N-Acetylglucosamine; n-glycans; Neurodegeneration; Neurodegenerative diseases; Original; pathology; Phosphorylation; Polysaccharides; Polysaccharides - metabolism; protein; protein glycosylation; Proteins; Signs and symptoms; site; tau; Tau protein; tau Proteins - cerebrospinal fluid; tau Proteins - metabolism
• ISSN: 1742-464X; 1742-4658; 1742-4658
• DOI: 10.1111/febs.15197

Alzheimer disease (AD) is a devastating disease and a global health problem, and current treatments are only symptomatic. A wealth of clinical studies support that the disease starts to develop decades before the first symptoms appear, emphasizing the importance of studying early changes for improving early diagnosis and guiding toward novel treatment strategies. Protein glycosylation is altered in AD but it remains to be clarified why these alterations occur and how they affect the disease development. Here, we used a glycomics approach to search for alterations in protein glycosylation in cerebrospinal fluid (CSF) in AD compared with nondemented controls. Using both matrix‐assisted laser desorption ionization‐time of flight and liquid chromatography–electrospray mass spectrometry, we observed an increase in N‐glycans carrying bisecting N‐acetylglucosamine in AD. Based on those findings, we designed an enzyme‐linked multiwell plate assay to quantify N‐glycans binding to the lectin Phaseolus vulgaris Erythroagglutinin (PHA‐E), which is specific for N‐glycans containing bisecting N‐acetylglucosamine. Using this assay, we found a similar increase in CSF in AD compared with controls. Further analysis of CSF from 242 patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or AD dementia revealed significantly increased binding to PHA‐E in MCI and AD compared to SCI. Interestingly, PHA‐E binding correlated with CSF levels of phosphorylated tau and total tau and this correlation was most prominent in the SCI group (R = 0.53–0.54). This study supports a link between N‐glycosylation, neurodegeneration, and tau pathology in AD and suggests that glycan biomarkers have potential to identify SCI cases at risk of developing AD. Glycomics analyses showed alterations in the N‐glycan pattern in cerebrospinal fluid (CSF) in Alzheimer disease as compared to controls. The levels of several N‐linked glycans carrying bisecting N‐acetylglucosamine were increased in AD. A multiwell plate enzyme‐linked lectin assay denoted enzyme‐linked lectin assay (ELLA) was developed based on these findings. Intriguingly, a correlation between ELLA data and tau levels was observed both in AD and in subjective cognitive impairment.