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Novel antibody against low-n oligomers of tau protein promotes clearance of tau in cells via lysosomes

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Mandelkow,  Eva-Maria
Neuronal Cytoskeleton and Alzheimer's Disease, Cooperations, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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Citation

Chandupatla, R. R., Flatley, A., Feederle, R., Mandelkow, E.-M., & Kaniyappan, S. (2020). Novel antibody against low-n oligomers of tau protein promotes clearance of tau in cells via lysosomes. Alzheimer's & Dementia, 6(1): e12097. doi:10.1002/trc2.12097.


Cite as: http://hdl.handle.net/21.11116/0000-0007-643E-4
Abstract
Introduction: Tau, a natively unfolded soluble protein, forms abnormal oligomers and insoluble filaments in several neurodegenerative diseases, including Alzheimer disease (AD). Tau-induced toxicity is mainly due to oligomers rather than monomers or fibrils.; Methods: We have developed monoclonal antibodies against purified low-n tau oligomers of the tau repeat domain as a tool to neutralize tau aggregation and toxicity. In vitro aggregation inhibition was tested by thioflavin S, dynamic light scattering (DLS), and atomic force microscopy (AFM). Using a split-luciferase complementation assay and fluorescence-activated cell sorting (FACS), the inhibition of aggregation was analyzed in an N2a cell model of tauopathy.; Results: Antibodies inhibited tau aggregation in vitro up to ~90% by blocking tau at an oligomeric state. Some antibodies were able to block tau dimerization/oligomerization in cells, as measured by a split-luciferase complementation assay. Antibodies applied extracellularly were internalized and led to sequestration of tau into lysosomes for degradation.; Discussion: Novel low-n tau oligomer specific monoclonal antibody inhibits Tau oligomerization in cells and promotes toxic tau clearance. © 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.