Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation | Acta Neuropathologica Communications | Full Text

Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation | Acta Neuropathologica Communications | Full Text

Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation

• Monika Zilkova, 
• Anna Nolle, 
• Branislav Kovacech, 
• Eva Kontsekova, 
• Petronela Weisova, 
• Peter Filipcik, 
• Rostislav Skrabana, 
• Michal Prcina, 
• Tomas Hromadka, 
• Ondrej Cehlar, 
• Gabriela Paulikova Rolkova, 
• Denisa Maderova, 
• Michal Novak, 
• Norbert Zilka & 
• Jeroen J. M. Hoozemans 

Acta Neuropathologica Communications volume 8, Article number: 74 (2020) Cite this article

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Abstract

Immunotherapies targeting pathological tau have recently emerged as a promising approach for treatment of neurodegenerative disorders. We have previously showed that the mouse antibody DC8E8 discriminates between healthy and pathological tau, reduces tau pathology in murine tauopathy models and inhibits neuronal internalization of AD tau species in vitro.

Here we show, that DC8E8 and antibodies elicited against the first-in-man tau vaccine, AADvac1, which is based on the DC8E8 epitope peptide, both promote uptake of pathological tau by mouse primary microglia. IgG1 and IgG4 isotypes of AX004, the humanized versions of DC8E8, accelerate tau uptake by human primary microglia isolated from post-mortem aged and diseased brains. This promoting activity requires the presence of the Fc-domain of the antibodies.

The IgG1 isotype of AX004 showed greater ability to promote tau uptake compared to the IgG4 isotype, while none of the antibody-tau complexes provoked increased pro-inflammatory activity of microglia. Our data suggest that IgG1 has better suitability for therapeutic development.