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Prion diseases are invariably fatal and infectious neurodegenerative diseases charac-terized by the conversion of the physiological cellular prion protein (PrPC) into its iso-form called scrapie prion protein (PrPSc). PrPSc has the tendency to form aggregates leading to progressive neuronal cell death, microglial activation and a spongiform de-generation of the central nervous system (CNS). Active and passive immunization strat-egies have been investigated in neurodegenerative disorders such as Alzheimer’s disease and in animal models of prion diseases. For Alzheimers- and Parkinsons disease, natu-rally occurring autoantibodies (nAbs) have been analyzed and hypothesized as potential treatment options. Therefore, this work aimed to investigate the mode of action of prion specific nAbs (nAbs-PrP) in vitro in prion diseases. In this study, we detected nAbs-PrP in human Serum and CSF of healthy subjects. These autoantibodies could be successfully purified from intravenous immunoglobulin (IVIg) by using affinity chromatography columns conjugated with the peptide PrP106-126 A117V. The existence of those antibodies in healthy subjects implies a physiological role of nAbs-PrP with respect to the conversion of PrPC into PrPSc. Indeed, we found nAbs-PrP to break down fibril formation of PrP106-126 A117V in a dose-dependent manner. Furthermore, nAbs-PrP were found to prevent PrP106-126 A117V induced toxicity in primary cortical neurons. We further examined the role of nAbs-PrP in microglia-mediated prion “clearance”. nAbs-PrP considerably enhanced the uptake of PrP106-126 A117V in microglial cells without inducing an inflammatory response or a loss of vitality. The application of several phagocytosis inhibitors gave first insights into the possible mechanisms underlying prion uptake in microglial cells. We found at least two separate mechanisms to be responsible for the nAbs-PrP-mediated PrP106-126 A117V uptake on the one hand and the uptake of fibrillary PrP106-126 A117V alone on the other hand. In summary, we found nAbs-PrP to interfere with the pathological processes underlying prion conversion and -toxicity in vitro. In our experiments, nAbs-PrP exhibited beneficial effects in terms of prion-“clearance” without inducing any detrimental side effects (e.g., inflammatory response) in microglia cells. Therefore, it might be worth to investigate the nAbs-PrP-mediated effect on the progression of prion diseases in vivo.