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.
Highlights
Several tau immunotherapeutic approaches are currently being developed as treatment for tau pathology in Alzheimer’s disease [44]
Mouse anti-tau antibody DC8E8 potentiates tau uptake into primary mouse microglia Our previous study showed that therapeutic anti-tau antibody DC8E8 recognizes pathological tau proteins in human AD brains, discriminates between diseased and healthy tau proteins, reduces formation of insoluble oligomerized tau and mature neurofibrillary tangles in a murine tauopathy model [23]
In this study we demonstrated that human microglia isolated from post-mortem human brains of patients suffering from AD and other neurodegenerative disorders were able to phagocytize pathological tau from extracellular space
Summary
Several tau immunotherapeutic approaches are currently being developed as treatment for tau pathology in Alzheimer’s disease [44]. The antibody-mediated uptake and degradation of pathological extracellular tau by microglia is an extensively discussed issue of tau immunotherapy due to the unclear contribution of microglia to the pathophysiology of. The selection of the isotype of a therapeutic antibody is an important aspect of its development, since antibody isotypes differently influence the receptor-mediated uptake by immune cells, induction of cytokines and engagement of various arms of the immune system [6, 12]. Choice of the optimal IgG isotype for a therapeutic anti-tau antibody depends both on efficacy and safety. Only a limited number of studies directly compared the potency of different anti-tau antibody isotypes
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
