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Abstract
Prior to the formation of amyloid fibrils, the pathological hallmark in tau-related neurodegenerative disease, tau monomers aggregate into a diverse range of oligomers. Granular tau oligomers, consisting of approximately 40 tau protein molecules, are present in the prefrontal cortex of patients at Braak stages I-II, preclinical stages of Alzheimer’s disease (AD). Antibodies to granular tau oligomers as antigens have not been reported. Therefore, we generated new rat monoclonal antibodies by immunization with granular tau oligomers. Three antibodies from different hybridoma clones showed stronger immunoreactivity to granular tau oligomers and tau fibrils compared with monomeric tau. Of the three antibodies, 2D6-2C6 showed 3000-fold greater immunoreactivity in P301L-tau transgenic (rTg4510) mice than in non-transgenic mice, while MC1 antibody, which detects pathological conformations of tau, showed a 5.5-fold increase. These results suggest that 2D6-2C6 recognizes aggregates more specifically than MC1. In AD subjects, 2D6-2C6 recognized neurofibrillary tangles and pretangles, and co-localized within AT8-positive cells containing phosphorylated tau aggregates. The epitope of 2D6-2C6 is the 423–430 amino acid (AA) sequence of C-terminal regions. Taken together, a novel monoclonal antibody, 2D6-2C6, generated by immunization with granular tau oligomers binds to tau aggregates at the 423–430 AA sequence.
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1 Gakushuin University, Laboratory for Alzheimer’s Disease, Department of Life Science, Faculty of Science, Tokyo, Japan (GRID:grid.256169.f) (ISNI:0000 0001 2326 2298)
2 Cell Engineering Corporation, Osaka, Japan (GRID:grid.256169.f)
3 Shiga University of Medical Science, Department of Diagnostics and Therapeutics for Brain Disease, Molecular Neuroscience Research Center, Otsu, Japan (GRID:grid.410827.8) (ISNI:0000 0000 9747 6806)
4 The University of Tokyo, Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2169 1048)
5 Cell Engineering Corporation, Osaka, Japan (GRID:grid.26999.3d); Osaka Metropolitan University, Graduate School of Engineering Division of Science and Engineering for Materials, Chemistry and Biology, Osaka, Japan (GRID:grid.26999.3d)
6 Aichi Medical University, Institute for Medical Science of Aging, Nagakute, Japan (GRID:grid.411234.1) (ISNI:0000 0001 0727 1557); Nagoya University, Department of Neurology, Nagoya, Japan (GRID:grid.27476.30) (ISNI:0000 0001 0943 978X)