Cargando…

Dynamics of Internalization and Intracellular Interaction of Tau Antibodies and Human Pathological Tau Protein in a Human Neuron-Like Model

We and others have shown in various in vivo, ex vivo and cell culture models that several tau antibodies interact with pathological tau within neurons. To further clarify this interaction in a dynamic human model, we differentiated SH-SY5Y cells with retinoic acid and BDNF to create a neuron-like mo...

Descripción completa

Detalles Bibliográficos
Autores principales: Shamir, Dov B., Deng, Yan, Wu, Qian, Modak, Swananda, Congdon, Erin E., Sigurdsson, Einar M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727311/
https://www.ncbi.nlm.nih.gov/pubmed/33324339
http://dx.doi.org/10.3389/fneur.2020.602292
_version_ 1783621073401544704
author Shamir, Dov B.
Deng, Yan
Wu, Qian
Modak, Swananda
Congdon, Erin E.
Sigurdsson, Einar M.
author_facet Shamir, Dov B.
Deng, Yan
Wu, Qian
Modak, Swananda
Congdon, Erin E.
Sigurdsson, Einar M.
author_sort Shamir, Dov B.
collection PubMed
description We and others have shown in various in vivo, ex vivo and cell culture models that several tau antibodies interact with pathological tau within neurons. To further clarify this interaction in a dynamic human model, we differentiated SH-SY5Y cells with retinoic acid and BDNF to create a neuron-like model. Therein, tau antibodies were primarily taken up by receptor-mediated endocytosis, and prevented toxicity of human brain-derived paired helical filament-enriched tau (PHF). Subsequently, we monitored in real-time the interaction of antibodies and PHF within endocytic cellular compartments. Cells were pre-treated with fluorescently-tagged PHF and then incubated with tau antibodies, 4E6, 6B2, or non-specific isotype control IgG1 labeled with a pH sensitive dye. The uptake and binding of the efficacious antibody, 4E6, to PHF occurred mainly within the soma, whereas the ineffective antibody, 6B2, and ineffective control IgG1, were visualized via the processes and showed limited colocalization with PHF within this period. In summary, we have developed a neuron-like model that clarifies the early intracellular dynamics of the interaction of tau antibodies with pathological tau, and identifies features associated with efficacy. Since the model is entirely human, it is suitable to verify the therapeutic potential of humanized antibodies prior to extensive clinical trials.
format Online
Article
Text
id pubmed-7727311
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-77273112020-12-14 Dynamics of Internalization and Intracellular Interaction of Tau Antibodies and Human Pathological Tau Protein in a Human Neuron-Like Model Shamir, Dov B. Deng, Yan Wu, Qian Modak, Swananda Congdon, Erin E. Sigurdsson, Einar M. Front Neurol Neurology We and others have shown in various in vivo, ex vivo and cell culture models that several tau antibodies interact with pathological tau within neurons. To further clarify this interaction in a dynamic human model, we differentiated SH-SY5Y cells with retinoic acid and BDNF to create a neuron-like model. Therein, tau antibodies were primarily taken up by receptor-mediated endocytosis, and prevented toxicity of human brain-derived paired helical filament-enriched tau (PHF). Subsequently, we monitored in real-time the interaction of antibodies and PHF within endocytic cellular compartments. Cells were pre-treated with fluorescently-tagged PHF and then incubated with tau antibodies, 4E6, 6B2, or non-specific isotype control IgG1 labeled with a pH sensitive dye. The uptake and binding of the efficacious antibody, 4E6, to PHF occurred mainly within the soma, whereas the ineffective antibody, 6B2, and ineffective control IgG1, were visualized via the processes and showed limited colocalization with PHF within this period. In summary, we have developed a neuron-like model that clarifies the early intracellular dynamics of the interaction of tau antibodies with pathological tau, and identifies features associated with efficacy. Since the model is entirely human, it is suitable to verify the therapeutic potential of humanized antibodies prior to extensive clinical trials. Frontiers Media S.A. 2020-11-26 /pmc/articles/PMC7727311/ /pubmed/33324339 http://dx.doi.org/10.3389/fneur.2020.602292 Text en Copyright © 2020 Shamir, Deng, Wu, Modak, Congdon and Sigurdsson. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Shamir, Dov B.
Deng, Yan
Wu, Qian
Modak, Swananda
Congdon, Erin E.
Sigurdsson, Einar M.
Dynamics of Internalization and Intracellular Interaction of Tau Antibodies and Human Pathological Tau Protein in a Human Neuron-Like Model
title Dynamics of Internalization and Intracellular Interaction of Tau Antibodies and Human Pathological Tau Protein in a Human Neuron-Like Model
title_full Dynamics of Internalization and Intracellular Interaction of Tau Antibodies and Human Pathological Tau Protein in a Human Neuron-Like Model
title_fullStr Dynamics of Internalization and Intracellular Interaction of Tau Antibodies and Human Pathological Tau Protein in a Human Neuron-Like Model
title_full_unstemmed Dynamics of Internalization and Intracellular Interaction of Tau Antibodies and Human Pathological Tau Protein in a Human Neuron-Like Model
title_short Dynamics of Internalization and Intracellular Interaction of Tau Antibodies and Human Pathological Tau Protein in a Human Neuron-Like Model
title_sort dynamics of internalization and intracellular interaction of tau antibodies and human pathological tau protein in a human neuron-like model
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727311/
https://www.ncbi.nlm.nih.gov/pubmed/33324339
http://dx.doi.org/10.3389/fneur.2020.602292
work_keys_str_mv AT shamirdovb dynamicsofinternalizationandintracellularinteractionoftauantibodiesandhumanpathologicaltauproteininahumanneuronlikemodel
AT dengyan dynamicsofinternalizationandintracellularinteractionoftauantibodiesandhumanpathologicaltauproteininahumanneuronlikemodel
AT wuqian dynamicsofinternalizationandintracellularinteractionoftauantibodiesandhumanpathologicaltauproteininahumanneuronlikemodel
AT modakswananda dynamicsofinternalizationandintracellularinteractionoftauantibodiesandhumanpathologicaltauproteininahumanneuronlikemodel
AT congdonerine dynamicsofinternalizationandintracellularinteractionoftauantibodiesandhumanpathologicaltauproteininahumanneuronlikemodel
AT sigurdssoneinarm dynamicsofinternalizationandintracellularinteractionoftauantibodiesandhumanpathologicaltauproteininahumanneuronlikemodel