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

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

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)85-96
Number of pages12
JournalNeurobiology of Disease
Volume104
DOIs
Publication statusPublished - Aug 2017
Externally publishedYes

Keywords

  • Dementia with Lewy bodies
  • Fibrils
  • Oligomers
  • Parkinson's disease
  • Passive immunization
  • α-synuclein

ASJC Scopus subject areas

  • Neurology

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