Physiologische und diagnostische Relevanz der N-Glykosylierung natürlich vorkommender Autoantikörper gegen das Beta-Amyloid Peptid bei der Alzheimer-Krankheit

Alzheimer’s disease as the most common neurodegenerative disorder is among others etio-pathologically characterized by a disrupted metabolic homeostasis of the protein Beta-Amy-loid (Aβ42). Interestingly, the human immunological repertoire contains naturally occurring autoantibodies that show Aβ42 reactivity (nAbs-Aβ42). Their existence indicate an Aβ42 proteo-stasis concerning, regulating and thus protective mechanism, for which quantitative and qual-itative properties of the autoantibodies are presumably of crucial importance. The N-glycosy-lation as an important qualitative feature of immunoglobulins affects among others their func-tional properties and may also be relevant for the physiological and protective functions of the nAbs-Aβ42. Simultaneously, potential alterations of the nAbs-Aβ42 glycosylation might be an essential pathological factor, which is why they could be used as a diagnostic marker for the identification of patients suffering from Alzheimer’s disease. Both central ideas have been pursued within the present work. Regarding nAbs, on the one hand, the protective effect on Aβ42 pathology and on the other hand a dependence of this physiological impact on an intact N-glycosylation could be demonstrated. These results addi-tionally provide important insights for future therapeutic strategies based on Aβ42 specific an-tibodies by suggesting the pattern and composition of N-glycans as crucial criteria for an ef-fective approach with low side-effects. Furthermore, using glycoengineering technology, im-munological processes might be specifically modulated for counteracting pathological changes of nAbs-Aβ42 glycosylation. Actually, such alterations have been found at the Fc-frag-ment of autoantibodies of patients suffering from Alzheimer’s disease in the course of a co-hort study. Based thereon a generalized linear prediction model has been developed, that enabled the classification of patients and controls with a sensitivity of 95% and specificity of 100%. Therefore, nAbs-Aβ42 Fc N-glycosylation should be considered as future biomarker after verifying the results in a validation cohort.