@article{4e2d483c0d2c44899a9980fa4ffbf2a0,
title = "TDP-43 interacts with amyloid-β, inhibits fibrillization, and worsens pathology in a model of Alzheimer{\textquoteright}s disease",
abstract = "TDP-43 inclusions are found in many Alzheimer{\textquoteright}s disease (AD) patients presenting faster disease progression and greater brain atrophy. Previously, we showed full-length TDP-43 forms spherical oligomers and perturbs amyloid-β (Aβ) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in Aβ aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited Aβ fibrillization at initial and oligomeric stages. Aβ fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for Aβ interaction. TDP-43 significantly enhanced Aβ{\textquoteright}s ability to impair long-term potentiation and, upon intrahippocampal injection, caused spatial memory deficit. Following injection to AD transgenic mice, TDP-43 induced inflammation, interacted with Aβ, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular Aβ in the brain of AD patients. We conclude that TDP-43 inhibits Aβ fibrillization through its interaction with Aβ and exacerbates AD pathology.",
author = "Shih, {Yao Hsiang} and Tu, {Ling Hsien} and Chang, {Ting Yu} and Kiruthika Ganesan and Chang, {Wei Wei} and Chang, {Pao Sheng} and Fang, {Yu Sheng} and Lin, {Yeh Tung} and Jin, {Lee Way} and Chen, {Yun Ru}",
note = "Funding Information: We thank research founding from Career Development Grant, Academia Sinica (AS-CDA-106-L01), Genomics Research Center, Academia Sinica, and Ministry of Science and Technology, Taiwan (MOST 108-2113-M-001-027). The work was supported in part by the U.S. National Institute on Aging grant P30 AG10129 (University of California Davis Alzheimer{\textquoteright}s Disease Research Center). We thank Dr. Hanna S. Yuan, Institute of Molecular Biology, Academia Sinica for providing pQE30 plasmids and E. coli strain M15. We thank Dr. Shu-Chuan Jao of the Biophysics Core Facility, funded by Academia Sinica Core Facility and Innovative Instrument Project (AS-CFII108-111), and Mr. Hong-Chang Chu in Dr. Ying-Da Wu{\textquoteright}s laboratory at Genomics Research Center, Academia Sinica for providing technical assistance of biolayer interferometry experiments. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
doi = "10.1038/s41467-020-19786-7",
language = "English",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}