Targeting alpha-synuclein by PD03 AFFITOPE (R) and Anle138b rescues neurodegenerative pathology in a model of multiple system atrophy: clinical relevance

Lemos, Miguel; Venezia, Serena; Refolo, Violetta; Heras-Garvin, Antonio; Schmidhuber, Sabine; Giese, Armin; Leonov, Andrei; Ryazanov, Sergey; Griesinger, Christian; Galabova, Gergana; Staffler, Guenther; Wenning, Gregor Karl und Stefanova, Nadia (2020): Targeting alpha-synuclein by PD03 AFFITOPE (R) and Anle138b rescues neurodegenerative pathology in a model of multiple system atrophy: clinical relevance. In: Translational Neurodegeneration, Bd. 9, Nr. 1, 38

Abstract

Background: Misfolded oligomeric alpha-synuclein plays a pivotal role in the pathogenesis of alpha-synucleinopathies including Parkinson's disease and multiple system atrophy, and its detection parallels activation of microglia and a loss of neurons in the substantia nigra pars compacta. Here we aimed to analyze the therapeutic efficacy of PD03, a new AFFITOPE (R) immunotherapy approach, either alone or in combination with Anle138b, in a PLP-alpha-syn mouse model. Methods: The PLP-alpha-syn mice were treated with PD03 immunotherapy, Anle138b, or a combination of two. Five months after study initiation, the mice underwent behavioral testing and were sacrificed for neuropathological analysis. The treatment groups were compared to the vehicle group with regard to motor performance, nigral neuronal loss, microglial activation and alpha-synuclein pathology. Results: The PLP-alpha-syn mice receiving the PD03 or Anle138b single therapy showed improvement of gait deficits and preservation of nigral dopaminergic neurons associated with the reduced alpha-synuclein oligomer levels and decreased microglial activation. The combined therapy with Anle138b and PD03 resulted in lower IgG binding in the brain as compared to the single immunotherapy with PD03. Conclusions: PD03 and Anle138b can selectively target oligomeric alpha-synuclein, resulting in attenuation of neurodegeneration in the PLP-alpha-syn mice. Both approaches are potential therapies that should be developed further for disease modification in alpha-synucleinopathies.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2047-9158
• Sprache: Englisch