Therapeutic antibody targeting microtubule-binding domain prevents neuronal internalization of extracellular tau via masking neuron surface proteoglycans

• Published in: Acta neuropathologica communications Vol. 7; no. 1; pp. 129 - 22
• Main Authors: Weisová, Petronela, Cehlár, Ondrej, Škrabana, Rostislav, Žilková, Monika, Filipčík, Peter, Kováčech, Branislav, Prčina, Michal, Wojčiaková, Ľubica, Fialová, Ľubica, Smolek, Tomáš, Kontseková, Eva, Žilka, Norbert, Novák, Michal
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 07-08-2019; BioMed Central; BMC
• Subjects: Advertising executives; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amino Acid Sequence; Analysis; Animals; Antibodies; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - metabolism; Antigenic determinants; Binding Sites - physiology; Biopharmaceuticals; Brain - drug effects; Brain - pathology; Drug Delivery Systems - trends; EDTA; Extracellular Space - drug effects; Extracellular Space - genetics; Extracellular Space - metabolism; Female; Health aspects; Heparan sulfate; Humans; Immunotherapy; Mechanism of action; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubules - drug effects; Microtubules - genetics; Microtubules - metabolism; Monoclonal antibodies; Nervous system diseases; Neurodegenerative diseases; Neurons; Neurons - drug effects; Neurons - metabolism; Novels; Pregnancy; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins; Proteoglycans - metabolism; Spreading; Sulfates; Surface science; Tau; tau Proteins - genetics; tau Proteins - metabolism; Heparan sulfate; Tau; Alzheimer’s disease; Mechanism of action; Immunotherapy; Spreading
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-019-0770-y

Pathologically altered tau protein is a common denominator of neurodegenerative disorders including Alzheimer's disease (AD) and other tauopathies. Therefore, promising immunotherapeutic approaches target and eliminate extracellular pathogenic tau species, which are thought to be responsible for seeding and propagation of tau pathology. Tau isoforms in misfolded states can propagate disease pathology in a template-dependent manner, proposed to be mediated by the release and internalization of extracellular tau. Monoclonal antibody DC8E8, binding four highly homologous and independent epitopes in microtubule-binding domain (MTBD) of diseased tau, inhibits tau-tau interaction, discriminates between healthy and pathologically truncated tau and reduces tau pathology in animal model in vivo. Here, we show that DC8E8 antibody acts via extracellular mechanism and does not influence viability and physiological functions of neurons. Importantly, in vitro functional assays showed that DC8E8 recognises pathogenic tau proteins of different size and origin, and potently blocks their entry into neurons. Next, we examined the mechanisms by which mouse antibody DC8E8 and its humanized version AX004 effectively block the neuronal internalization of extracellular AD tau species. We determined a novel mode of action of a therapeutic candidate antibody, which potently inhibits neuronal internalization of AD tau species by masking of epitopes present in MTBD important for interaction with neuron surface Heparan Sulfate Proteoglycans (HSPGs). We show that interference of tau-heparane sulfate interaction with DC8E8 antibody via steric hindrance represents an efficient and important therapeutic approach halting tau propagation.