Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
J Alzheimers Dis. 2014;38(3):567-79. doi: 10.3233/JAD-131088.
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.
基于血液的抗淀粉样β（Aβ）免疫球蛋白（IgG）和外周炎症是与阿尔茨海默病（AD）发展相关的因素。通过 IgG-Fc N-糖链结构的改变，IgG 的功能可以从抗炎性急剧转变为促炎性。在此，我们测试了 AD 发展过程中血浆 IgG-Fc 糖基化是否确实发生了改变。研究了 23 名对照组、58 名稳定轻度认知障碍（SMCI）患者、34 名进行性（P）MCI 患者和 31 名 AD 患者的年龄匹配样本。应用无糖蛋白富集的无标记 shotgun 蛋白质组学技术。定量了 IgG1 的 EEQYNSTYR 和 IgG2 的 EEQFNSTFR 肽上的聚糖，并将其丰度与总 IgGn 糖型丰度归一化。采用单变量和多变量统计方法研究了患者组与 IgG 糖型丰度以及炎症调节蛋白丰度之间的相关性。结果发现，AD 患者的复杂半乳糖基化和唾液酸化形式的丰度较低，差异具有统计学意义（p ≤ 0.05）。对于女性，糖型复杂性的降低与疾病进展相关，但在 AD 发病前男性则出现相反的变化。主成分分析（PCA；男性：R2X(cum) = 0.65，Q2(cum) = 0.34；女性：R2X(cum) = 0.62，Q2(cum) = 0.36）证实了男性（对照组、SMCI 和 AD）和女性（PMCI）之间的性别相似性（对于 PMCI 则存在差异），以及炎症性蛋白标志物、AD、女性 PMCI 和截断的 IgG-Fc 糖型之间的密切相关性。AD 发病前观察到的性别差异可能表明女性抑制外周炎症的能力较低，这可能导致疾病进展加剧。
