Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-020-19786-7
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Funding
- Academia Sinica [AS-CDA-106-L01]
- Genomics Research Center, Academia Sinica
- Ministry of Science and Technology, Taiwan [MOST 108-2113-M-001-027]
- U.S. National Institute on Aging [P30 AG10129]
- Academia Sinica Core Facility and Innovative Instrument Project [AS-CFII108-111]
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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-beta (A beta) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in A beta aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited A beta fibrillization at initial and oligomeric stages. A beta fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for A beta interaction. TDP-43 significantly enhanced A beta '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 A beta, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular A beta in the brain of AD patients. We conclude that TDP-43 inhibits A beta fibrillization through its interaction with A beta and exacerbates AD pathology. TDP-43 inclusions are observed in Alzheimer's disease. Here the authors show that TDP-43 interacts with amyloid-beta and inhibits fibrillization in vitro and exacerbates Alzheimer's disease pathology in animal models.
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