Please use this identifier to cite or link to this item:
http://dx.doi.org/10.25673/113747
Title: | TDP-43 pathology is associated with increased tau burdens and seeding |
Author(s): | Tomé, Sandra O. Tsaka, Grigoria Ronisz, Alicja Ospitalieri, Simona Gawor, Klara Aragão Gomes, Luis Otto, Markus ![]() Arnim, Christine ![]() Damme, Philip Bosch, Ludo Estifanos Ghebremedhin ![]() Laureyssen, Celeste Sleegers, Kristel Vandenberghe, Rik ![]() Rousseau, Frederic Schymkowitz, Joost Thal, Dietmar ![]() |
Issue Date: | 2023 |
Type: | Article |
Language: | English |
Abstract: | Background: Most Alzheimer’s Disease (AD) cases also exhibit limbic predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), besides amyloid-β plaques and neurofibrillary tangles (NFTs) containing hyperphosphorylated tau (p-tau). LATE-NC is characterized by cytoplasmic aggregates positive for pathological TDP-43 and is associated with more severe clinical outcomes in AD, compared to AD cases lacking TDP-43 pathology TDP-43: AD(LATE-NC-). Accumulating evidence suggests that TDP-43 and p-tau interact and exhibit pathological synergy during AD pathogenesis. However, it is not yet fully understood how the presence of TDP-43 affects p-tau aggregation in symptomatic AD. Methods: In this study, we investigated the impact of TDP-43 proteinopathy on p-tau pathology with different approaches: histologically, in a human post-mortem cohort (n = 98), as well as functionally using a tau biosensor cell line and TDP-43A315T transgenic mice. Results: We found that AD cases with comorbid LATE-NC, AD(LATE-NC+), have increased burdens of pretangles and/or NFTs as well as increased brain levels of p-tau199, compared to AD(LATE-NC-) cases and controls. The burden of TDP-43 pathology was also correlated with the Braak NFT stages. A tau biosensor cell line treated with sarkosyl-insoluble, brain-derived homogenates from AD(LATE-NC+) cases displayed exacerbated p-tau seeding, compared to control and AD(LATE-NC-)-treated cells. Consistently, TDP-43A315T mice injected with AD(LATE-NC+)-derived extracts also exhibited a more severe hippocampal seeding, compared to the remaining experimental groups, albeit no TDP-43 aggregation was observed. Conclusions: Our findings extend the current knowledge by supporting a functional synergy between TDP-43 and p-tau. We further demonstrate that TDP-43 pathology worsens p-tau aggregation in an indirect manner and increases its seeding potential, probably by increasing p-tau levels. This may ultimately contribute to tau-driven neurotoxicity and cell death. Because most AD cases present with comorbid LATE-NC, this study has an impact on the understanding of TDP-43 and tau pathogenesis in AD and LATE, which account for the majority of dementia cases worldwide. Moreover, it highlights the need for the development of a biomarker that detects TDP-43 during life, in order to properly stratify AD and LATE patients. |
URI: | https://opendata.uni-halle.de//handle/1981185920/115703 http://dx.doi.org/10.25673/113747 |
Open Access: | ![]() |
License: | ![]() |
Journal Title: | Molecular neurodegeneration |
Publisher: | Biomed Central |
Publisher Place: | London |
Volume: | 18 |
Original Publication: | 10.1186/s13024-023-00653-0 |
Page Start: | 1 |
Page End: | 18 |
Appears in Collections: | Open Access Publikationen der MLU |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
s13024-023-00653-0.pdf | 2.63 MB | Adobe PDF | ![]() View/Open |