Aug 9, 2019

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

Acta Neuropathologica Communications
Petronela WeisováMichal Novak

Abstract

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 internalizatio...Continue Reading

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Mentioned in this Paper

In Vivo
Tauopathies
Size
Denomination
Tau-protein Kinase Activity
7-methyl-1,5,7-triazabicyclo(4,4,0)dec-5-ene
Extracellular
Proteoglycan
Alzheimer's Disease
Administration @ Physiological Systems and Anatomical Regions @ Introduction @ Central Vein @ Open @ Immunotherapeutic

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