Abstract
Several tau antibody therapies are now in clinical trials and numerous other tau antibodies are in various stages of preclinical development to treat Alzheimer’s disease and related tauopathies. This involves long-term studies in mouse models that are necessary but time consuming and typically provide only a limited mechanistic understanding of how the antibodies work and why some are not effective. Live cellular imaging with fluorescently tagged pathological tau proteins and tau antibodies provides a valuable insight into their dynamic interaction outside or within the cell. Furthermore, this acute technique may have predictive validity to assess the potential efficacy of different tau antibodies in neutralizing and/or clearing tau aggregates, and can likely be applied to other amyloid diseases. Overall, it should facilitate identifying candidate antibodies for more detailed long-term validation. Due to the human origin of the model, it may be particularly useful to characterize humanized antibodies that utilize receptor-mediated uptake to reach their intracellular target.
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References
Pedersen JT, Sigurdsson EM (2015) Tau immunotherapy for Alzheimer’s disease. Trends Mol Med 21(6):394–402
Spencer B, Masliah E (2014) Immunotherapy for Alzheimer’s disease: past, present and future. Front Aging Neurosci 6:114
Yu YJ, Watts RJ (2013) Developing therapeutic antibodies for neurodegenerative disease. Neurotherapeutics 10(3):459–472
Gu J, Congdon EE, Sigurdsson EM (2013) Two novel tau antibodies targeting the 396/404 region are primarily taken up by neurons and reduce tau protein pathology. J Biol Chem 288(46):33081–33095
Funk KE, Mirbaha H, Jiang H, Holtzman DM, Diamond MI (2015) Distinct therapeutic mechanisms of tau antibodies: promoting microglial clearance vs. blocking neuronal uptake. J Biol Chem 290(35):21652–21662
Luo W, Liu W, Hu X, Hanna M, Caravaca A, Paul SM (2015) Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Sci Rep 5:11161
Holmes BB, Diamond MI (2014) Prion-like properties of tau protein: the importance of extracellular tau as a therapeutic target. J Biol Chem 289(29):19855–19861
Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM (2007) Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci 27(34):9115–9129
Congdon EE, Gu J, Sait HB, Sigurdsson EM (2013) Antibody uptake into neurons occurs primarily via clathrin-dependent Fcgamma receptor endocytosis and is a prerequisite for acute tau protein clearance. J Biol Chem 288(49):35452–35465
Congdon E, Lin Y, Rajamohamedsait H, Shamir D, Rajamohamedsait W, Rasool S, Gonzalez V, Lavenga J, Gu J, Hoeffer C, Sigurdsson E (2016) Affinity of tau antibodies for soluble pathological tau species but not their immunogen or insoluble tau aggregates predicts in vivo and ex vivo efficacy. Mol Neurodegener 11(1):62
Krishnamurthy PK, Deng Y, Sigurdsson EM (2011) Mechanistic studies of antibody-mediated clearance of tau aggregates using an ex vivo brain slice model. Front Psychiatry 2:59
Shamir DB, Rosenqvist N, Rasool S, Pedersen JT, Sigurdsson EM (2016) Internalization of tau antibody and pathological tau protein detected with a flow cytometry multiplexing approach. Alzheimers Dement 12(10):1098–1107
Collin L, Bohrmann B, Gopfert U, Oroszlan-Szovik K, Ozmen L, Gruninger F (2014) Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer’s disease. Brain 137(Pt 10):2834–2846
Kondo A, Shahpasand K, Mannix R, Qiu J, Moncaster J, Chen CH, Yao Y, Lin YM, Driver JA, Sun Y, Wei S, Luo ML, Albayram O, Huang P, Rotenberg A, Ryo A, Goldstein LE, Pascual-Leone A, McKee AC, Meehan W, Zhou XZ, Lu KP (2015) Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 523(7561):431–436
Krishnaswamy S, Lin Y, Rajamohamedsait WJ, Rajamohamedsait HB, Krishnamurthy P, Sigurdsson EM (2014) Antibody-derived in vivo imaging of tau pathology. J Neurosci 34(50):16835–16850
Lee VMY, Wang J, Trojanowski JQ (1999) Purification of paired helical filament tau and normal tau from human brain tissue. Meth Enzymol 309:81–89
Rostagno A, Ghiso J (2009) Isolation and biochemical charecterization of amyloid plaques and paired helical filaments. Curr Protoc Cell Biol 44:3.33.1–3.33.33
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Shamir, D.B., Deng, Y., Sigurdsson, E.M. (2018). Live Imaging of Pathological Tau Protein and Tau Antibodies in a Neuron-Like Cellular Model. In: Sigurdsson, E., Calero, M., Gasset, M. (eds) Amyloid Proteins. Methods in Molecular Biology, vol 1779. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7816-8_22
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DOI: https://doi.org/10.1007/978-1-4939-7816-8_22
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