한빛사논문
Ly Thi Huong Luu Le 1,2, Jeeyoung Lee 1,3, Dongjoon Im 4, Sunha Park 2, Kyoung-Doo Hwang 2,5, Jung Hoon Lee 1, Yanxialei Jiang 1,6, Yong-Seok Lee 2,5,7, Young Ho Suh 2,7, Hugh I Kim 4, Min Jae Lee 1,2,8
1Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, South Korea.
2Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, 03080, South Korea.
3Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, South Korea.
4Department of Chemistry, Korea University, Seoul, 02841, South Korea.
5Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, South Korea.
6School of Medicine, Linyi University, Linyi, 276000, China.
7Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea.
8Ischemic/Hypoxic Disease Institute, Convergence Research Center for Dementia, Seoul National University College of Medicine, Seoul, 03080, South Korea.
L.T.H.L.L., J.L., D.I., S.P., K.-D.H., contributed equally to this work.
CORRESPONDING AUTHORS: Yong-Seok Lee, Young Ho Suh, Hugh I. Kim, Min Jae Lee
Abstract
In tauopathy conditions, such as Alzheimer's disease (AD), highly soluble and natively unfolded tau polymerizes into an insoluble filament; however, the mechanistic details of this process remain unclear. In the brains of AD patients, only a minor segment of tau forms β-helix-stacked protofilaments, while its flanking regions form disordered fuzzy coats. Here, it is demonstrated that the tau AD nucleation core (tau-AC) sufficiently induced self-aggregation and recruited full-length tau to filaments. Unexpectedly, phospho-mimetic forms of tau-AC (at Ser324 or Ser356) show markedly reduced oligomerization and seeding propensities. Biophysical analysis reveal that the N-terminus of tau-AC facilitates the fibrillization kinetics as a nucleation motif, which becomes sterically shielded through phosphorylation-induced conformational changes in tau-AC. Tau-AC oligomers are efficiently internalized into cells via endocytosis and induced endogenous tau aggregation. In primary hippocampal neurons, tau-AC impaired axon initial segment plasticity upon chronic depolarization and is mislocalized to the somatodendritic compartments. Furthermore, it is observed significantly impaired memory retrieval in mice intrahippocampally injected with tau-AC fibrils, which corresponds to the neuropathological staining and neuronal loss in the brain. These findings identify tau-AC species as a key neuropathological driver in AD, suggesting novel strategies for therapeutic intervention.
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