Abstract
In prion disease, a profound microglial activation that precedes neurodegeneration has been observed in the CNS. It is still not fully elucidated whether microglial activation has beneficial effects in terms of prion clearance or whether microglial cells have a mainly detrimental function through the release of pro-inflammatory cytokines. To date, no disease-modifying therapy exists. Several immunization attempts have been performed as one therapeutic approach. Recently, naturally occurring autoantibodies against the prion protein (nAbs-PrP) have been detected. These autoantibodies are able to break down fibrils of the most commonly used mutant prion variant PrP106-126 A117V and prevent PrP106-126 A117V-induced toxicity in primary neurons. In this study, we examined the phagocytosis of the prion peptide PrP106-126 A117V by primary microglial cells and the effect of nAbs-PrP on microglia. nAbs-PrP considerably enhanced the uptake of PrP106-126 A117V without inducing an inflammatory response in microglial cells. PrP106-126 A117V uptake was at least partially mediated through scavenger receptors. Phagocytosis of PrP106-126 A117V with nAbs-PrP was inhibited by wortmannin, a potent phosphatidylinositol 3-kinase inhibitor, indicating a separate uptake mechanism for nAbs-PrP mediated phagocytosis. These data suggest the possible mechanisms of action of nAbs-PrP in prion disease.
Highlights
Prion diseases are a group of transmissible neurodegenerative diseases characterized by progressive neuronal cell death, astrogliosis and microglial activation, leading to a spongiform degeneration of the central nervous system (CNS)
We found that microglial cells phagocytosed fluorescein isothiocyanate (FITC)-labeled PrP106-126 A117V fibrils in a time-dependent manner, with a maximum uptake after 6 hours when normalized to untreated cells (Fig. 2A)
Because we demonstrated that Naturally occurring autoantibodies (nAbs)-PrP, as well as the monoclonal anti-PrP antibody 3F4, prevented PrP106-126 A117V fibril formation, we investigated the effect of nAbs-PrP on the phagocytic ability of microglia
Summary
Prion diseases are a group of transmissible neurodegenerative diseases characterized by progressive neuronal cell death, astrogliosis and microglial activation, leading to a spongiform degeneration of the central nervous system (CNS). The hallmark of the disease is the conversion of the physiological cellular prion protein (PrPC) into its isoform called scrapie prion protein (PrPSc). This conversion is followed by further oligomerization and fibrillation, which has a pathological effect on cells. Autoantibodies against the prion protein (nAbs-PrP) have been detected [3]. They are able to block the fibrillation into aggregates of prion peptides in vitro and can further reduce the toxicity of the peptides on cultured primary neurons. Occurring autoantibodies (nAbs) are part of the innate immune system and make up 2/3 of the total IgG in humans [4]. nAbs have been detected against other aggregating proteins, including b-amyloid (Ab), tau and a-synuclein, and their role in neurodegenerative diseases is a major topic of current research [3,5,6,7]
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