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

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.


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Policy information about availability of computer code Data collection Data analysis Yun-Ru Chen Oct 15, 2020 For ThT: The data were collected by SoftMax Pro 6.3 in SpectraMax M5, Molecule Devices For CD: The spectra were collected by Spectra Manager 2.0 in Jasco J-815 spectropolarimeter For Western blot: ImageQuart was used For ELISA: The reading was collected by SoftMax Pro 6.3 in SpectraMax M5, Molecule Devices For Octet: The signals were obtained by Octet RED96 system with the Data Analysis Software (ForteBio). For animal behavior Study: The behavior studies were recorded and analyzed by EthoVision video tracking system (Noldus Information Technology, Wageningen, Netherlands) For LTP: The fEPSP were recorded by MED-P515A/5 (1 mm) probe (Alpha MED Scientific Inc., Osaka, Japan) with Alpha MED64 MEA system. For IHC: The images were taken by Aperio AT2 Digital Pathology Scanner (Leica Biosystem, Mannheim, Germany) For IF: The images were taken by Aperio FL Digital Pathology Scanner (Leica Biosystem, Mannheim, Germany). For Abeta assembly and IP: The blots were detected by Imagequant LAS4000 system (GE Healthcare, Life sciences, Hungary). For human Staining: The images were taken by Aperio CS2 Digital Pathology Scanner (Leica Biosystem).
For Octet Red96, KD value was obtained by data fitting using the Data Analysis Software (ForteBio). For animal Study: The behavior data were recorded and analyzed by EthoVision video tracking system (Noldus Information Technology, Wageningen, Netherlands) For LTP: The fEPSP slopes were quantified by MED64 Mobius Software For IHC: The images were analyzed by ImageJ 1.8.0_60 (NIH, USA) For IF: The images were analyzed by ImageJ 1.8.0_60 (NIH, USA) For Abeta assembly and IP: The blotting signal was quantified by ImageJ 1.8.0_60 (NIH, USA).
All data except for Octet data were further plotted by GraphPad Prism version 7.0.

October 2018
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The sample sizes in each study were described in the manuscript. To determine the size, we referenced the previous study to determine the sample size1 according to the previous study and suggested by the Academia Sinica Institutional Animal Care and Utilization Committee (IACUC). The minimum require sample of each group is 4 for protein injection study to against the null hypothesis. Previous study indicated that APP/PS1!E9 (B6C3-Tg (APPswe, PSEN1dE9) 85Dbo/Mmjax mice have 20% mortality around 5-month-old2, so we used more than double sample size from 4 to 10 for the transgenic mice injection study.

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October 2018 Antibodies Antibodies used Validation All antibodies used were described in 'Methods' section of the manuscript and supplementary information. The detailed information is listed in validation.