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Fc N-glycosylation of autoreactive Aβ antibodies as a blood-based biomarker for Alzheimer's disease
Yannick Kronimus 1, Alexandra Albus 1, Mike Hasenberg 2, Bernd Walkenfort 2, Marc Seifert 3, Bettina Budeus 3, Janine Gronewold 4, Dirk M Hermann 4, J Alexander Ross 1, Günter Lochnit 5, Sebastian P Galuska 6, Katrin Marcus 7, Barbara Sitek 7 8, Jens Klotsche 9, David Mengel 1 10, Sascha Neumann 1, Richard Dodel 1
Abstract:
Introduction: Naturally occurring autoantibodies (nAbs) against the pathologic isoform of amyloid beta (Aβ42 ) were found in body fluids and indicate a systemic B cell response that may prevent Alzheimer's disease (AD) onset. N-glycans attached to immunoglobulin G-Fab/Fc fragments are features that influence their mechanism of action. The aim was to study the role of N-glycans in nAbs-Aβ42 .
Methods: nAbs-Aβ42 were isolated from AD patients and age-/sex-matched controls (n = 40) and immunoglobulin preparations. Glycosylated/deglycosylated nAbs-Aβ42 were analyzed for their effect on Aβ42 's aggregation, toxicity, and phagocytosis. Glycan structure was analyzed using matrix assisted laser desorption ionization time of flight mass spectrometry.
Results: Deglycosylation of nAbs-Aβ42 had a major impact on Aβ42 's aggregation/toxicity/phagocytosis. The glycan structure showed considerable differences between AD and controls. We were able to predict disease status with a sensitivity/specificity of 95% (confidence interval [CI]: 76.4-99.7%)/100% (CI: 83.9-100%).
Discussion: N-glycosylation has been identified as a critical attribute maintaining the beneficial effects of autoreactive Aβ antibodies. These data have consequences for the development of monocloncal Aβ antibodies and may open new avenues for diagnostics.
Methods: nAbs-Aβ42 were isolated from AD patients and age-/sex-matched controls (n = 40) and immunoglobulin preparations. Glycosylated/deglycosylated nAbs-Aβ42 were analyzed for their effect on Aβ42 's aggregation, toxicity, and phagocytosis. Glycan structure was analyzed using matrix assisted laser desorption ionization time of flight mass spectrometry.
Results: Deglycosylation of nAbs-Aβ42 had a major impact on Aβ42 's aggregation/toxicity/phagocytosis. The glycan structure showed considerable differences between AD and controls. We were able to predict disease status with a sensitivity/specificity of 95% (confidence interval [CI]: 76.4-99.7%)/100% (CI: 83.9-100%).
Discussion: N-glycosylation has been identified as a critical attribute maintaining the beneficial effects of autoreactive Aβ antibodies. These data have consequences for the development of monocloncal Aβ antibodies and may open new avenues for diagnostics.
