title: Blood plasma IgG Fc glycans are significantly altered in Alzheimer's disease and progressive mild cognitive impairment.
abstract: Blood-based anti-amyloid-β (Aβ) immunoglobulins (IgGs) and peripheral inflammation are factors correlating with development of Alzheimer's disease (AD). IgG functionality can drastically change from anti- to pro-inflammatory via alterations in the IgG-Fc N-glycan structure. Herein, we tested if IgG-Fc glycosylation in plasma is indeed altered during the development of AD. Samples from age-matched subjects of 23 controls, 58 patients with stable mild cognitive impairment (SMCI), 34 patients with progressive (P)MCI, and 31 patients with AD were investigated. Label-free shotgun proteomics was applied without glycoprotein enrichment. Glycans on peptides EEQYNSTYR (IgG1) and EEQFNSTFR (IgG2) were quantified, and their abundances were normalized to total IgGn glycoform abundance. Univariate and multivariate statistics were employed to investigate the correlations between the patients groups and the abundances of the IgG glycoforms as well as those of inflammatory mediating proteins. Significant differences (p ≤ 0.05) were found, with a lower abundance of complex galactosylated and sialylated forms in AD. For females, a decline in glycoform complexity correlated with disease progress but an inverse change was found in males prior to the onset of AD. Principal component analysis (PCA; Males: R(2)X(cum) = 0.65, Q(2)(cum) = 0.34; Females: R(2)X(cum) = 0.62, Q(2)(cum) = 0.36), confirmed the gender similarities (for controls, SMCI and AD) as well as differences (for PMCI), and showed a close correlation between pro-inflammatory protein markers, AD, female PMCI, and truncated IgG-Fc glycans. The differences observed between genders prior to the onset of AD may indicate a lower ability in females to suppress peripheral inflammation, which may lead to exacerbated disease progression.
authors.affiliation: Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Lundström
authors.forename: Hongqian
authors.initials: H
authors.lastname: Yang
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Lyutvinskiy
authors.forename: Dorothea
authors.initials: D
authors.lastname: Rutishauser
authors.forename: Sanna-Kaisa
authors.initials: SK
authors.lastname: Herukka
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.forename: Roman A
authors.initials: RA
authors.lastname: Zubarev
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood*; D060825:Cognitive Dysfunction / Q000097:blood*; D003165:Complement System Proteins / Q000378:metabolism; D005260:Female; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000097:blood*; D007074:Immunoglobulin G / Q000097:blood* / Q000737:chemistry / Q000145:classification; D008297:Male; D009843:Oligoribonucleotides / Q000276:immunology; D011134:Polysaccharides / Q000276:immunology*; D025341:Principal Component Analysis; D012737:Sex Factors; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D009843:Oligoribonucleotides; D011134:Polysaccharides; D051918:Sialic Acid Binding Ig-like Lectin 2; D003165:Complement System Proteins
keywords: Fc; glycoproteomics; glycosylation; immunoglobulin; inflammation