한빛사논문
- 조회488
Ha-Lim Song,1 Na-Young Kim,1 Jaewan Park,2 Meong Il Kim,2 Yu-Na Jeon,3 Se-Jong Lee,3 Kwangmin Cho,1 Young-Lim Shim,1 Kyoung-Hye Lee,1 Yeon-Seon Mun,1 Jung-A Song,1 Min-Seok Kim,1 Chan-Gi Pack,4 Minkyo Jung,5 Hyemin Jang,6 Duk L. Na,6 Minsun Hong,2 Dong-Hou Kim,3 and Seung-Yong Yoon1,3,7
1ADEL Institute of Science & Technology (AIST), ADEL Inc., Seoul, South Korea.
2Division of Biological Science and Technology, Yonsei University, Wonju, South Korea.
3Department of Brain Science and
4Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
5Neural Circuits Research Group, Korea Brain Research Institute, Daegu, South Korea.
6Samsung Alzheimer’s Convergence Research Center, Department of Neurology, Neuroscience Center, Samsung Medical Center, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, South Korea.
7Stem Cell Immunomodulation Research Center, University of Ulsan College of Medicine, Seoul, South Korea.
HLS, NYK, and JP contributed equally to this work.
Address correspondence to: Seung-Yong Yoon or Dong-Hou Kim, Or to: Minsun Hong
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.
논문정보
- Research article
- 2023년 04월 (BRIC 등록일 2023-04-18)
- 국내 연구진
- 의약학 > 신경의학
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