Monoclonal antibody Y01 prevents tauopathy progression induced by lysine 280–acetylated tau in cell and mouse models
Ha-Lim Song, … , Dong-Hou Kim, Seung-Yong Yoon
Ha-Lim Song, … , Dong-Hou Kim, Seung-Yong Yoon
Published March 14, 2023
Citation Information: J Clin Invest. 2023;133(8):e156537. https://doi.org/10.1172/JCI156537.
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Research Article Neuroscience Therapeutics

Monoclonal antibody Y01 prevents tauopathy progression induced by lysine 280–acetylated tau in cell and mouse models

Abstract

The spatiotemporal pattern of the spread of pathologically modified tau through brain regions in Alzheimer’s disease (AD) can be explained by prion-like cell-to-cell seeding and propagation of misfolded tau aggregates. Hence, to develop targeted therapeutic antibodies, it is important to identify the seeding- and propagation-competent tau species. The hexapeptide 275VQIINK280 of tau is a critical region for tau aggregation, and K280 is acetylated in various tauopathies, including AD. However, the mechanism that links tau acetylated on lysine 280 (tau-acK280) to subsequent progression to neurodegenerative disease remains unclear. Here, we demonstrate that tau-acK280 is critical for tau propagation processes including secretion, aggregation, and seeding. We developed an antibody, Y01, that specifically targets tau-acK280 and solved the crystal structure of Y01 in complex with an acK280 peptide. The structure confirmed that Y01 directly recognizes acK280 and the surrounding residues. Strikingly, upon interaction with acetylated tau aggregates, Y01 prevented tauopathy progression and increased neuronal viability in neuron cultures and in tau-Tg mice through antibody-mediated neutralization and phagocytosis, respectively. Based on our observations that tau-acK280 is a core species involved in seeding and propagation activities, the Y01 antibody that specifically recognizes acK280 represents a promising therapeutic candidate for AD and other neurodegenerative diseases associated with tauopathy.

Authors

Ha-Lim Song, Na-Young Kim, Jaewan Park, Meong Il Kim, Yu-Na Jeon, Se-Jong Lee, Kwangmin Cho, Young-Lim Shim, Kyoung-Hye Lee, Yeon-Seon Mun, Jung-A Song, Min-Seok Kim, Chan-Gi Pack, Minkyo Jung, Hyemin Jang, Duk L. Na, Minsun Hong, Dong-Hou Kim, Seung-Yong Yoon

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Figure 4

Amelioration of cognitive deficits and pathology by i.c.v. infusion of mouse-Y01.

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Amelioration of cognitive deficits and pathology by i.c.v. infusion of m...
(A) Schematic diagram of the passive immunization experimental design. (B–D) Two weeks after the start of infusions, behavioral tests were performed during the next 2 weeks of infusion. (B) Nest building test. (C) Y maze. (D) Morris water maze. WT + IgG, n = 4; tau-P301L + IgG, n = 6; tau-P301L + Y01, n = 6; all mice were male. NE, SE, SW, and NW indicate northeast, southeast, southwest, and northwest quadrants. Target quadrant: NW. (E) Immunoblots of Tau5 and Y01 in RAB fractions, RIPA fractions, and formic acid (FA) fractions of the cortex from immunized mice. WT + IgG, tau-P301L + IgG, tau-P301L + Y01, n = 2 per group; all mice were male. (F) Immunoblots of Tau5, tau-pS396, and Y01 in the cortex from immunized mice. The lanes were run on the same gel but were noncontiguous. (G) Quantification of Tau5, tau-pS396, and Y01 protein levels normalized to β-actin. WT + IgG, n = 4; tau-P301L + IgG, n = 5; tau-P301L + Y01, n = 5; all mice were male. Statistical analysis was performed by 1-way ANOVA followed by Tukey’s multiple-comparison test. *P < 0.05, **P < 0.01, ***P < 0.001. The error bars represent the SEM.