Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy

Abstract

Synucleinopathies represent a group of neurodegenerative disorders which are characterized by intracellular accumulation of aggregated α-synuclein. α-synuclein misfolding and oligomer formation is considered a major pathogenic trigger in these disorders. Therefore, targeting α-synuclein species represents an important candidate therapeutic approach. Our aim was to analyze the biological effects of passive immunization targeting α-synuclein and to identify the possible underlying mechanisms in a transgenic mouse model of oligodendroglial α-synucleinopathy. We used PLP-α-synuclein mice overexpressing human α-synuclein in oligodendrocytes. The animals received either antibodies that recognize α-synuclein or vehicle. Passive immunization mitigated α-synuclein pathology and resulted in reduction of total α-synuclein in the hippocampus, reduction of intracellular accumulation of aggregated α-synuclein, particularly significant in the spinal cord. Lowering of the extracellular oligomeric α-synuclein was associated with reduction of the density of activated iba1-positive microglia profiles. However, a shift toward phagocytic microglia was seen after passive immunization of PLP-α-synuclein mice. Lowering of intracellular α-synuclein was mediated by autophagy degradation triggered after passive immunization in PLP-α-synuclein mice. In summary, the study provides evidence for the biological efficacy of immunotherapy in a transgenic mouse model of oligodendroglial synucleinopathy. The different availability of the therapeutic antibodies and the variable load of α-synuclein pathology in selected brain regions resulted in differential effects of the immunotherapy that allowed us to propose a model of the underlying mechanisms of antibody-aided α-synuclein clearance.

MSA: From basic mechanisms to experimental therapeutics

“…↓ α-syn oligomers ↓ GCIs ↓ Demyelination ↑ Neuroprotection ↑ Motor function [145]. Passive immunization α-syn aggregation In PLP-hα-syn mice: ↓ α-syn oligomers ↓ GCIs ↑ Phagocytic microglia [148]. α-syn degradation enhancers Lithium α-syn clearance In toxin-induced models of PD: A phase II was performed but had to be terminated due to severe adverse effects [160].…”

“…In addition, despite transgenic animal models have contributed to identify important aspects of the disease, they artificially overexpress α-syn in oligodendrocytes, thus concealing the mechanism which triggers MSA and the accumulation of α-syn [83,204,205]. Novel strategies targeting α-syn aggregation, such as α-syn immunotherapy and small molecules, hold, however, promising therapeutic potential that still have to be evaluated in human trials [123][124][125]145,148]. In order to do that, it will be necessary to improve the design of clinical studies by selecting patient cohorts as homogeneous as possible and at early stages of the disease, before the neurodegenerative process is too advanced and neuronal rescue is still feasible.…”

“…Results suggested good immunogenicity, safety and tolerability of both vaccines in MSA and PD [146,147]. Moreover, a recent study by Kallab and colleagues demonstrated biological efficacy of passive immunization in PLP-hα-syn mice, where the infusion of antibodies against oligomeric hα-syn resulted in a reduction of intracellular aggregated α-syn and extracellular soluble oligomeric species, associated with an increase of phagocytic microglia [148].…”

Immunotherapies in Huntington's disease and α-Synucleinopathies

“…Immunization with a monoclonal antibody that targeted oligomeric/prefibrillary forms of α-Syn (mAb47) mitigates the accumulation of oligomeric αSyn in the brain stem and improved motor behavioral performance (134). Recently, Kallab et al showed three antibodies (Syn-F1, Syn-O1, and Syn-O4) that specifically target oligomeric α-Syn and damped motor behavior deficit and neuroinflammation (135).…”

“…Although therapeutic targets against α-Syn are beneficial in cellular and rodent models of PD (130,135), their translational efficacy in human clinical trials still poses a major challenge as underlying mechanisms are not fully understood.…”