Prion Peptide Uptake in Microglial Cells – The Effect of Naturally Occurring Autoantibodies against Prion Protein

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.

Immunization of cervidized transgenic mice with multimeric deer prion protein induces self-antibodies that antagonize chronic wasting disease infectivity in vitro

“…Interestingly, CpG post-immune sera decreased the conversion activity of CWD prions in RT-QuIC assay only very marginally, much less than the blocking effect caused by Mdi and Ddi post-immune sera at the identical dilution. The subtle effect of control sera may be explained, at least partially, by the existence of some autoantibodies against PrP as reported by previous studies 41 , 42 . Whether using deer or mouse substrate did not affect the inhibitory effect of post-immune sera (Fig.…”

The neuroprotective role of microglial cells against amyloid beta‐mediated toxicity in organotypic hippocampal slice cultures

“…The analysis of ThioT-positive areas of microglia-depleted OHSCs following Aβ 1-42 treatment for 48 h did not result in a significant difference compared to non-treated OHSCs ( Figure 5C). In contrast, significant increases in hippocampal areas positive for ThioT were observed To further investigate the impact of microglial Aβ 1-42 uptake on neuronal survival in OHSCs, we applied cytochalasin D, a blocker of actin polymerization that inhibits the phagocytic activity of microglia (64,74) at a concentration that was barely neurotoxic in OHSC (52). Treatment with cytochalasin D resulted in a significant increase in the hippocampal area that was positive for ThioT, suggesting efficient inhibition of microglial Aβ 1-42 intake ( Figure 5D).…”

Extending the functional characteristics of naturally occurring autoantibodies against β-Amyloid, Prion Protein and α-Synuclein

“…For ELISA and ThT assays monomeric Aβ was used. For PrP experiments, a short fragment of the prion protein with a single mutation (PrP106-126 A117V), was applied, which was successfully used previously in aggregation studies and already showed oligomerization [ 30 , 13 , 24 ]. Furthermore, this PrP version exhibits some pathological characteristics of PrP sc , like fibril formation [ 31 ].…”