Fig. 8

Antibody blocks neuronal internalization of human AD tau by masking HSPGs recognition sites via steric hindrance. a Proposed mechanism of action of therapeutic candidate antibody DC8E8 and its humanized version AX004. Antibody binds to tetratop in the microtubule binding region (MTBR) with a common amino acid pattern HxPGGG (yellow boxes). AD tau contains several heparan sulfate proteoglycan binding sequences that are present in close proximity to DC8E8 tetratop recognition site. Here shown based on determined interaction of heparin with either four repeat MTBR (bold) or with three repeat MTBR (grey bold) [103]. Additionally, lysine residues responsible for interaction of full-length tau with heparin are presented as underlined. Particular strong interaction was identified for lysine-rich region downstream of R4 [27, 80]. We hypothesize that the binding of antibody affects the tau residues in the vicinity of its epitopes (green boxes). b Soluble heparin chain (stick model, pink carbon atoms, PDB ID: 3IRJ) is bound to the fuzzy coat of the PHF core (green, modified according PDB ID 5O3L) [25] along its binding motifs on tau represented by hexapeptides ²⁷⁵VQIINK²⁸⁰ and ³⁰⁶VQIVYK³¹¹ (highlighted in blue, as arrows) [27, 80]. The interaction of DC8E8 antibody (gray surface model) with disordered part of PHF tau (epitopes R1 and R2 highlighted in red) blocks adjacent heparin binding motifs. Such arrangement inhibits neuronal internalization by DC8E8-mediated blocking of the interaction between heparan sulfate binding motifs on tau to neuronal surface HSPGs via steric hindrance. For three tau chains, fuzzy-coat disordered repeats R1 and R2 are shown. All molecules are presented in full proportion. Model of Pembrolizumab, a full length IgG4 antibody (PDB ID 5DK3) was used as a proxy for DC8E8 structure