TDP-43 interacts with amyloid-β, inhibits fibrillization, and worsens pathology in a model of Alzheimer’s disease

Yao-Hsiang Shih, Ling-Hsien Tu, Ting-Yu Chang, Kiruthika Ganesan, Wei-Wei Chang, Pao-Sheng Chang, Yu-Sheng Fang, Yeh-Tung Lin, Lee-Way Jin and Yun-Ru Chen ()
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Yao-Hsiang Shih: Academia Sinica, 128, Academia Road, Section 2, Nankang District
Ling-Hsien Tu: Academia Sinica, 128, Academia Road, Section 2, Nankang District
Ting-Yu Chang: Academia Sinica, 128, Academia Road, Section 2, Nankang District
Kiruthika Ganesan: Academia Sinica, 128, Academia Road, Section 2, Nankang District
Wei-Wei Chang: Academia Sinica, 128, Academia Road, Section 2, Nankang District
Pao-Sheng Chang: Academia Sinica, 128, Academia Road, Section 2, Nankang District
Yu-Sheng Fang: Academia Sinica, 128, Academia Road, Section 2, Nankang District
Yeh-Tung Lin: Academia Sinica, 128, Academia Road, Section 2, Nankang District
Lee-Way Jin: Alzheimer’s Disease Center, 2805 50th Street, University of California Davis Medical Center
Yun-Ru Chen: Academia Sinica, 128, Academia Road, Section 2, Nankang District

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract TDP-43 inclusions are found in many Alzheimer’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’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.

Date: 2020
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DOI: 10.1038/s41467-020-19786-7

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