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.

• Authors: Omar El-Agnaf, Cassia Overk, Edward Rockenstein, Michael Mante, Jazmin Florio, Anthony Adame, Nishant Vaikath, Nour Majbour, Seung-Jae Lee, Changyoun Kim, Eliezer Masliah, Robert A Rissman
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 104 Pg. 85-96 (Aug 2017) ISSN: 1095-953X [Electronic] United States
• PMID: 28476636 (Publication Type: Journal Article)
• Copyright: Published by Elsevier Inc.

Chemical References

• Aif1 protein, mouse
• Antibodies
• Calcium-Binding Proteins
• Glial Fibrillary Acidic Protein
• Microfilament Proteins
• Synaptophysin
• alpha-Synuclein

Topics

• Analysis of Variance
• Animals
• Antibodies (therapeutic use)
• Calcium-Binding Proteins (metabolism)
• Cell Cycle (genetics)
• Cell Line, Tumor
• Dementia (genetics, immunology, therapy)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Exploratory Behavior (physiology)
• Female
• Glial Fibrillary Acidic Protein (metabolism)
• Immunotherapy (methods)
• Mice
• Mice, Transgenic
• Microfilament Proteins (metabolism)
• Microscopy, Confocal
• Neuroblastoma (pathology)
• Parkinsonian Disorders (genetics, immunology, therapy)
• Synaptophysin (metabolism)
• alpha-Synuclein (genetics, immunology, metabolism)