TDP-43 pathology is associated with increased tau burdens and seeding

Author:

Tomé Sandra O.ORCID,Tsaka Grigoria,Ronisz Alicja,Ospitalieri Simona,Gawor Klara,Gomes Luis Aragão,Otto Markus,von Arnim Christine A. F.,Van Damme Philip,Van Den Bosch Ludo,Ghebremedhin Estifanos,Laureyssen Celeste,Sleegers Kristel,Vandenberghe RikORCID,Rousseau FredericORCID,Schymkowitz JoostORCID,Thal Dietmar RudolfORCID

Abstract

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.

Funder

BrightFocus Foundation

KU Leuven

Fonds Wetenschappelijk Onderzoek

Vlaamse Impulsfinanciering voor Netwerken voor Dementie-onderzoek

Alzheimer's Association

Mady Browaeys fonds voor Onderzoek naar Frontotemporale Degeneratie

National Institute on Aging

Internationale Stichting Alzheimer Onderzoek

Vlaams Instituut voor Biotechnologie

Publisher

Springer Science and Business Media LLC

Subject

Cellular and Molecular Neuroscience,Neurology (clinical),Molecular Biology

Reference84 articles.

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