Biology subjects

Aguzzi, A.

Publications and source records attributed to Aguzzi, A..

3 recordsLinked to original sources

bioRxiv2018

A bispecific immunotweezer prevents soluble PrP oligomers and abolishes prion toxicity

Antibodies to the prion protein, PrP, represent a promising therapeutic approach against prion diseases but the neurotoxicity of certain anti-PrP antibodies has caused concern. Here we describe scPOM-bi, a bispecific antibody designed to function as a molecular prion tweezer. scPOM-bi combines the complementarity-determining regions of the neurotoxic antibody POM1 and the neuroprotective POM2, which bind the globular domain (GD) and flexible tail (FT) respectively. We found that scPOM-bi confers protection to prion-infected organotypic cerebellar slices even when prion pathology is already conspicuous. Moreover, scPOM-bi prevents the formation of soluble oligomers that correlate with neurotoxic PrP species. Simultaneous targeting of both GD and FT was more effective than concomitant treatment with the individual molecules or targeting the tail alone, possibly by preventing the GD from entering a toxic-prone state. We conclude that simultaneous binding of the GD and flexible tail of PrP results in strong protection from prion neurotoxicity and may represent a promising strategy for anti-prion immunotherapy.\n\nAuthor summaryAntibody immunotherapy is considered a viable strategy against prion disease. We previously showed that antibodies against the so-called globular domain of Prion Protein (PrP) can cause PrP dependent neurotoxicity; this does not happen for antibodies against the flexible tail of PrP, which therefore ought to be preferred for therapy.\n\nHere we show that simultaneous targeting of both globular domain and flexible tail by a bispecific, combination of a toxic and a non-toxic antibody, results in stronger protection against prion toxicity, even if the bispecific is administered when prion pathology is already conspicuous.\n\nWe hypothesize that neurotoxicity arises from binding to specific \"toxicity triggering sites\" in the globular domain. We designed our bispecific with two aims: i) occupying one such site and preventing prion or other factors from docking to it and ii) binding to the flexible tail to engage the region of PrP necessary for neurotoxicity.\n\nWe also show that neurotoxic antibodies cause the formation of soluble PrP oligomers that cause toxicity on PrP expressing cell lines; these are not formed in the presence of prion protective antibodies. We suggest that these soluble species might play a role in prion toxicity, similarly to what is generally agreed to happen in other neurodegenerative disorders.

molecular biology↗

bioRxiv2018

Unaltered prion disease in mice lacking developmental endothelial locus-1 (Del 1)

Progression of prion diseases is driven by the accumulation of prions in the brain. Ablation of microglia or deletion of the eat-me-signal milk-fat globule EGF factor VIII (Mfge8) accelerate prion pathogenesis, suggesting that microglia defends the brain by phagocytosing prions. Like Mfge8, Developmental endothelial locus-1 (Del-1) is a secreted protein that acts as an opsonin bridging phagocytes and apoptotic cells to facilitate phagocytosis. We therefore asked whether Del-1 might play a role in controlling prion pathogenesis. We first determined the expression pattern of Del-1 in mice, and found that the brain expresses the highest level of Del-1. In mouse brains, Del-1 was mainly expressed by neurons. We then assessed the anti-inflammatory and phagocytosis-promoting functions of Del-1 in prion disease, and determined whether Del-1 complements Mfge8 in prion clearance in mice with a C57BL/6J genetic background. We found that Del-1 deficiency did not change prion disease progression and lesion patterns. Also, prion clearance and PrPSc deposition were unaltered in Del-1 deficient mice. Additionally, prioninduced neuroinflammation was not affected by Del-1 deficiency. We conclude that Del-1 is not a major determinant of prion pathogenesis in this context.

neuroscience↗

bioRxiv2018

Lymphocyte activation gene 3 (Lag3) is upregulated by prions but does not contribute to disease

Prion diseases, Alzheimers disease and Parkinsons disease (PD) are fatal degenerative disorders that share common neuropathological and biochemical features, including the aggregation of pathological protein conformers. Lymphocyte activation gene 3 (Lag3, also known as CD223) is a member of the immunoglobulin superfamily of receptors expressed on peripheral immune cells, microglia and neurons, which serves as a receptor for -synuclein aggregates in PD. Here we examined the possible role of Lag3 in the pathogenesis of prion diseases. Through quantitative real-time PCR and RNA-sequencing, we found that the expression levels of Lag3 were relatively low in the adult mouse brains, yet its expression was increased after prion infection. However, we failed finding significant differences regarding the incubation time, PrPSc load, neurodegeneration, astrocyte and microglia reactions and inflammatory gene expression between the Lag3 knockout mice and wild-type littermate controls after prion infection. We conclude that loss of Lag3 has no significant influence on prion disease pathogenesis. Considering that Lag3 is an immune checkpoint receptor, our results suggest that immune checkpoint inhibition (an increasingly prevalent therapeutic modality against many types of cancer) might not exert positive or negative effects on the progression of prion diseases.

neuroscience↗