Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy

Abstract

Disorders with progressive accumulation of α-synuclein (α-syn) are a common cause of dementia and parkinsonism in the aging population. Accumulation and propagation of α-syn play a role in the pathogenesis of these disorders. Previous studies have shown that immunization with antibodies that recognize C-terminus of α-syn reduces the intra-neuronal accumulation of α-syn and related deficits in transgenic models of synucleinopathy. These studies employed antibodies that recognize epitopes within monomeric and aggregated α-syn that were generated through active immunization or administered via passive immunization. However, it is possible that more specific effects might be achieved with antibodies recognizing selective species of the α-syn aggregates. In this respect we recently developed antibodies that differentially recognized various oligomers (Syn-O1, -O2, and -O4) and fibrilar (Syn-F1 and -F2) forms of α-syn. For this purpose wild-type α-syn transgenic (line 61) mice were immunized with these 5 different antibodies and neuropathologically and biochemically analyzed to determine which was most effective at reducing α-syn accumulation and related deficits. We found that Syn-O1, -O4 and -F1 antibodies were most effective at reducing accumulation of α-syn oligomers in multiple brain regions and at preventing neurodegeneration. Together this study supports the notion that selective antibodies against α-syn might be suitable for development new treatments for synucleinopathies such as PD and DLB.

Antibodies against alpha‐synuclein: tools and therapies

“…Furthermore, we have demonstrated that immunization with conformation‐specific monoclonal antibodies reduces α‐syn accumulation and related deficits in wild‐type α‐syn transgenic (line 61) mice (El‐Agnaf et al . ). Moreover, the antibodies were most effective at reducing accumulation of α‐syn oligomers in multiple brain regions and at preventing neurodegeneration (El‐Agnaf et al .…”

“…Moreover, the antibodies were most effective at reducing accumulation of α‐syn oligomers in multiple brain regions and at preventing neurodegeneration (El‐Agnaf et al . ). Therefore, immunotherapeutic targeting of α‐syn oligomers holds considerable promise in the continued search for disease‐modifying therapies for α‐synucleinopathies.…”

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

“…Recent work comparing the effectiveness of targeting either oligomers or fibrils validates these in vitro observations as the greatest alleviation of pathology in vivo was achieved via immunotherapy targeted against early‐stage oligomers (El‐Agnaf et al . ). Similarly, the α‐Syn fibrillation inhibitor epigallocatechin gallate has been shown to reduce the membrane interaction and permeabilization of oligomers from the extracellular environment (Lorenzen et al .…”

“…As with intracellular aimed trials of immunotherapy, antibodies targeted toward oligomeric a-Syn have also proven successful at blocking the toxicity of extracellular a-Syn in SH-SY5Y cells in vitro (Emadi et al 2009) and at facilitating the clearance of extracellular aggregates via microglial scavenging (Bae et al 2012). Recent work comparing the effectiveness of targeting either oligomers or fibrils validates these in vitro observations as the greatest alleviation of pathology in vivo was achieved via immunotherapy targeted against early-stage oligomers (El-Agnaf et al 2017). Similarly, the a-Syn fibrillation inhibitor epigallocatechin gallate has been shown to reduce the membrane interaction and permeabilization of oligomers from the extracellular environment (Lorenzen et al 2014).…”

The good and bad of therapeutic strategies that directly target α‐synuclein

“…68 In a following multicenter, randomized, double-blind, placebo-controlled trial, assessing multiple ascending doses of PRX002 in mild-to-moderate idiopathic PD patients aged 40 to 80 years (Hoehn and Yahr Stages 1-3), both single and multiple doses of this antibody resulted safe, were well tolerated, and produced robust binding of peripheral α-syn as well as dose-dependent increases of PRX002 in cerebrospinal fluid. 67 Several other studies addressed the development of antibodies targeting α-syn, 70,71 including strategies targeting oligomeric forms, [72][73][74] the C-terminus of the protein, 75 or exploiting passive immunization. [76][77][78] Interestingly, some of these approaches were also found to efficiently reduce α-syn propagation.…”