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

• Published in: The Journal of clinical investigation Vol. 133; no. 8; pp. 1 - 15
• Main Authors: Song, Ha-Lim, Kim, Na-Young, Park, Jaewan, Kim, Meong Il, Jeon, Yu-Na, Lee, Se-Jong, Cho, Kwangmin, Shim, Young-Lim, Lee, Kyoung-Hye, Mun, Yeon-Seon, Song, Jung-A, Kim, Min-Seok, Pack, Chan-Gi, Jung, Minkyo, Jang, Hyemin, Na, Duk L, Hong, Minsun, Kim, Dong-Hou, Yoon, Seung-Yong
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 17-04-2023
• Subjects: Advertising executives; Alzheimer Disease; Alzheimer's disease; Animal models; Animals; Antibodies; Antibodies, Monoclonal - pharmacology; Biomedical research; Brain; Brain - metabolism; Care and treatment; Cell culture; Crystal structure; Diagnosis; Disease Models, Animal; Health aspects; Keystone species; Lysine; Mice; Monoclonal antibodies; Nervous system diseases; Neurodegenerative Diseases; Neurons; Neuroscience; Pathology; Phagocytosis; Prevention; Propagation; Protein seeding; Tau protein; Tau proteins; tau Proteins - genetics; tau Proteins - metabolism; Tauopathies - drug therapy; Therapeutics; South Korea; Neuroscience; Alzheimer disease; Immunotherapy; Therapeutics
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI156537

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.