Antibody mediated inhibition of Tau aggregation in in-vitro and in neuronal cells

Ram Reddy Chandupatla1, Regina Feederle2, Eckhard Mandelkow1, Eva Maria Mandelkow1, Senthilvelrajan Kaniyappan1

1 DZNE, Bonn
2 Helmholtz Zentrum, München

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The repeat domain of Tau protein with the pro-aggregant mutation ΔK280 (TauRDΔK280) induces toxicity in transgenic mice and organotypic hippocampal slice culture models. Oligomeric forms of TauRDΔK280 indeed cause severe synaptotoxicity. One of the strategies to prevent such toxic effects is to inhibit the aggregation of Tau or neutralize the toxicity by antibodies. We generated monoclonal antibodies against purified low-n oligomers of TauRDΔK280, revealing antibody affinities in the μM to nM range. Several antibodies were used to check their ability to inhibit the aggregation of Tau in vitro by biophysical and microscopic methods. Two antibodies had the ability to inhibit the aggregation of hT40P301L Tau in in vitro analyzed by ThS and DLS. Structural analysis by AFM revealed that Tau fibrils or higher aggregates were absent in the presence of these antibodies. A split-luciferase complementation assay in N2a cells revealed that Tau aggregation was inhibited if the antibodies were applied extracellularly at an early stage. By confocal microscopy we observed that antibodies were internalized into N2a cells and co-localized with lysosomes. Only one antibody was able to recruit the cytosolic Tau into lysosomes for degradation. Preclinical studies are underway and this particular potential antibody can be used for immunotherapy studies.