Active poly-GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model

Zhou, Qihui; Mareljic, Nikola; Michaelsen, Meike; Parhizkar, Samira; Heindl, Steffanie; Nuscher, Brigitte; Farny, Daniel; Czuppa, Mareike; Schludi, Carina; Graf, Alexander; Krebs, Stefan; Blum, Helmut; Feederle, Regina; Roth, Stefan; Haass, Christian; Arzberger, Thomas; Liesz, Arthur und Edbauer, Dieter (2019): Active poly-GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model. In: EMBO Molecular Medicine, e10919

Abstract

The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non-canonical translation of the expanded repeat results in abundant poly-GA inclusion pathology throughout the CNS. (GA)(149)-CFP expression in mice triggers motor deficits and neuroinflammation. Since poly-GA is transmitted between cells, we investigated the therapeutic potential of anti-GA antibodies by vaccinating (GA)(149)-CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin-(GA)(10) conjugates and pre-aggregated carrier-free (GA)(15). Only ovalbumin-(GA)(10) immunization induced a strong anti-GA response. The resulting antisera detected poly-GA aggregates in cell culture and patient tissue. Ovalbumin-(GA)(10) immunization largely rescued the motor function in (GA)(149)-CFP transgenic mice and reduced poly-GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin-(GA)(10)-immunized poly-GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP-43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1757-4676
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198