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Zhou, Q.* ; Mareljic, N.* ; Michaelsen, M.* ; Parhizkar, S.* ; Heindl, S.* ; Nuscher, B.* ; Farny, D.* ; Czuppa, M.* ; Schludi, C.* ; Graf, A.* ; Krebs, S.* ; Blum, H.* ; Feederle, R. ; Roth, S.* ; Haass, C.* ; Arzberger, T.* ; Liesz, A.* ; Edbauer, D.*

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

EMBO Mol. Med. 12:e10919 (2020)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Amyotrophic Lateral Sclerosis ; C9orf72 ; Frontotemporal Dementia ; Immunotherapy ; Neurodegeneration; Dipeptide-repeat Proteins; To-cell Transmission; Alpha-synuclein; Hexanucleotide Repeat; Cerebrospinal-fluid; Alzheimers-disease; Kappa-b; Tau; Pathology; Immunotherapy
ISSN (print) / ISBN 1757-4676
e-ISSN 1757-4684
Zeitschrift EMBO Molecular Medicine
Quellenangaben Band: 12, Heft: 2, Seiten: , Artikelnummer: e10919 Supplement: ,
Verlag Wiley
Verlagsort Chichester
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) CF Monoclonal Antibodies (CF-MAB)