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

• Published in: Molecular neurodegeneration Vol. 18; no. 1; pp. 1 - 71
• Main Authors: Tomé, Sandra O, 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, Rik, Rousseau, Frederic, Schymkowitz, Joost, Thal, Dietmar Rudolf
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 30-09-2023; BioMed Central; BMC
• Subjects: Advertising executives; Age; Alzheimer's disease; Amyotrophic lateral sclerosis; Autopsies; Autopsy; Biosensors; Brain; Cell death; Co-pathologies seeding; Comorbidity; Dementia; Dementia disorders; Detectors; Encephalopathy; Ethics; Genetic engineering; Hippocampus; Injections; Ketamine; LATE-NC; Neurodegenerative diseases; Neurofibrillary tangles; Neuropathology; Neurotoxicity; Pathogenesis; Pathology; Protein aggregation; Protein seeding; Proteins; Tau; Tau protein; TDP-43; Transgenic animals; Transgenic mice; Working groups; β-Amyloid; Belgium; United States > US; Germany
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-023-00653-0

Background Most Alzheimer's Disease (AD) cases also exhibit limbic predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), besides amyloid-[beta] 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-43.sup.A315T 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-43.sup.A315T 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. Keywords: Alzheimer's Disease, TDP-43, LATE-NC, Co-pathologies seeding, Tau, Protein aggregation