Prions induce lethal neurodegeneration and consist of PrP^Sc, an aggregated conformer of the cellular prion protein PrP^C. Antibody-derived ligands to the globular domain of PrP^C (collectively termed GDL) are also neurotoxic. Here we show that GDL and prion infections activate the same pathways. Firstly, both GDL and prion infection of cerebellar organotypic cultured slices (COCS) induced the production of reactive oxygen species (ROS). Accordingly, ROS scavenging, which counteracts GDL toxicity in vitro and in vivo, prolonged the lifespan of prion-infected mice and protected prion-infected COCS from neurodegeneration. Instead, neither glutamate receptor antagonists nor inhibitors of endoplasmic reticulum calcium channels abolished neurotoxicity in either model. Secondly, antibodies against the flexible tail (FT) of PrP^C reduced neurotoxicity in both GDL-exposed and prion-infected COCS, suggesting that the FT executes toxicity in both paradigms. Thirdly, the PERK pathway of the unfolded protein response was activated in both models. Finally, 80% of transcriptionally downregulated genes overlapped between prion-infected and GDL-treated COCS. We conclude that GDL mimic the interaction of PrP^Sc with PrP^C, thereby triggering the downstream events characteristic of prion infection. Prion diseases are a group of infectious, invariably fatal neurodegenerative diseases. Progress in developing therapeutics is slow, partly because animal models of prion diseases require stringent biosafety and are very slow. We recently found that treatment of cerebellar slices with antibodies targeting the globular domain (GD ligands) of the prion protein (PrP) is neurotoxic. Here we compared this model to prion infection, and describe striking similarities. Both models involved the production of reactive oxygen species, and antioxidants could reverse the toxicity in cerebellar slices and even prolong the survival time of prion-infected mice. Antibodies targeting the flexible tail of PrP that prevent toxicity of GD ligands reduced the toxicity induced by prions. Endoplasmic reticulum stress, which is involved in prion toxicity, is also found in GD-ligand induced neurotoxicity. Finally, changes of gene expression were similar in both models. We conclude that prion infection and GD ligands use converging neurotoxic pathways. Because GD ligands induce toxicity within days rather than months and do not pose biosafety hazards, they may represent a powerful tool for furthering our understanding of prion pathogenesis and also for the discovery of antiprion drugs.

Antibodies against the prion protein PrP^C can antagonize prion replication and neuroinvasion, and therefore hold promise as possible therapeutics against prion diseases. However, the safety profile of such antibodies is controversial. It was originally reported that the monoclonal antibody D13 exhibits strong target-related toxicity, yet a subsequent study contradicted these findings. We have reported that several antibodies against certain epitopes of PrP^C, including antibody POM1, are profoundly neurotoxic, yet antibody ICSM18, with an epitope that overlaps with POM1, was reported to be innocuous when injected into mouse brains. In order to clarify this confusing situation, we assessed the neurotoxicity of antibodies D13 and ICSM18 with dose-escalation studies using diffusion-weighted magnetic resonance imaging and various histological techniques. We report that both D13 and ICSM18 induce rapid, dose-dependent, on-target neurotoxicity. We conclude that antibodies directed to this region may not be suitable as therapeutics. No such toxicity was found when antibodies against the flexible tail of PrP^C were administered. Any attempt at immunotherapy or immunoprophylaxis of prion diseases should account for these potential untoward effects. The human prion disease, Creutzfeldt-Jakob disease (CJD), is a progressive neurodegenerative syndrome. Although far less prevalent, CJD shows many molecular and clinical similarities to Alzheimer's disease, such as the buildup of protein aggregates in the brain and the absence of effective treatments. Many attempts at immunotherapy for Alzheimer’s disease are being reported in specialized journals and in the lay press, and have been linked to strong hopes for a cure. The same therapeutic strategy appears plausible for Creutzfeldt-Jakob disease, and indeed, there are some encouraging preclinical studies. However, there have also been reports that antibodies against the prion protein (PrP^C) can also wreak damage on the brain. We have gathered evidence that various antiprion antibodies vary not only in their efficacy but also in their potential to induce serious untoward effects. In a dose-escalation study, we report that all antibodies against a set of epitopes in the globular domain of the prion protein display acute neurotoxicity. These issues need to be carefully assessed before considering any clinical studies involving human subjects.

Anti-myelin-associated glycoprotein (MAG) neuropathy is an antibody-mediated polyneuropathy. We correlated clinical features, immunoglobulin (Ig) M blood levels, IgM deposition and axonal degeneration in skin biopsies of anti-MAG neuropathy patients. By confocal microscopy, IgM deposits were found exclusively within perineurium-enclosed nerves; they were not found on single, non-perineurium-ensheathed myelinated axons. There was a linear correlation between IgM accumulation in nerve fascicles with IgM blood levels but not with anti-MAG antibody titer or disease duration. Axons with specific IgM deposits had signs of axonal damage, including neurofilament disintegration. Nodal structures were intact even at sites where the axons showed pathologic changes. Ultrastructural analysis revealed degeneration of myelinating Schwann cells. Taken together, these findings suggest that inanti-MAG neuropathy patients, IgM deposits are entrapped within cutaneous perineurium-ensheathed nerve bundles where they accumulate in the endoneurial space. High local IgM levels in the endoneurium may be required for IgM deposition on myelin and subsequent axonal injury and degeneration. This study underlines theimportance of early, effective anti-B-cell treatments for preventing progression of this neuropathy.

Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here, we identified > 6,000 PrP‐binding antibodies in a synthetic human Fab phage display library, 49 of which we characterized in detail. Antibodies directed against the flexible tail of PrP conferred neuroprotection against infectious prions. We then mined published repertoires of circulating B cells from healthy humans and found antibodies similar to the protective phage‐derived antibodies. When expressed recombinantly, these antibodies exhibited anti‐PrP reactivity. Furthermore, we surveyed 48,718 samples from 37,894 hospital patients for the presence of anti‐PrP IgGs and found 21 high‐titer individuals. The clinical files of these individuals did not reveal any enrichment of specific pathologies, suggesting that anti‐PrP autoimmunity is innocuous. The existence of anti‐prion antibodies in unbiased human immunological repertoires suggests that they might clear nascent prions early in life. Combined with the reported lack of such antibodies in carriers of disease‐associated PRNP mutations, this suggests a link to the low incidence of spontaneous prion diseases in human populations.