TDP-43 and Tau Oligomers in Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia

• Published in: Neurobiology of disease Vol. 146; p. 105130
• Main Authors: Montalbano, Mauro, McAllen, Salome, Cascio, Filippa Lo, Sengupta, Urmi, Garcia, Stephanie, Bhatt, Nemil, Ellsworth, Anna, Heidelman, Eric A., Johnson, Omar D., Doskocil, Samantha, Kayed, Rakez
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2020; Elsevier
• Subjects: Aggregation; Neurodegeneration; Oligomer; Tau; Tauopathies; TDP-43; TauO; TauM; AD; ALS; Tau; BDT43Os; Oligomer; Aggregation; Tauopathies; TDP-43Os; HMW; Neurodegeneration; iHEK; RBPs; TDP-43; FTD; LMW; mTDP-43; TauF; MAPT; TARDBP
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2020.105130

Proteinaceous aggregates are major hallmarks of several neurodegenerative diseases. Aggregates of post-translationally modified transactive response (TAR)-DNA binding protein 43 (TDP-43) in cytoplasmic inclusion bodies are characteristic features in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Recent studies have also reported TDP-43 aggregation in Alzheimer's disease (AD). TDP-43 is an RNA/DNA binding protein (RBP) mainly present in the nucleus. In addition to several RBPs, TDP-43 has also been reported in stress granules in FTD and ALS pathologies. Despite knowledge of cytoplasmic mislocalization of TDP-43, the cellular effects of TDP-43 aggregates and their cytotoxic mechanism(s) remain to be clarified. We hypothesize that TDP-43 forms oligomeric assemblies that associate with tau, another key protein involved in ALS and FTD. However, no prior studies have investigated the interactions between TDP-43 oligomers and tau. It is therefore important to thoroughly investigate the cross-seeding properties and cellular localization of both TDP-43 and tau oligomers in neurodegenerative diseases. Here, we demonstrate the effect of tau on the cellular localization of TDP-43 in WT and P301L tau-inducible cell models (iHEK) and in WT HEK-293 cells treated exogenously with soluble human recombinant tau oligomers (Exo-rTauO). We observed cytoplasmic TDP-43 accumulation o in the presence of tau in these cell models. We also studied the occurrence of TDP-43 oligomers in AD, ALS, and FTD human brain tissue using novel antibodies generated against TDP-43 oligomers as well as generic TDP-43 antibodies. Finally, we examined the cross-seeding property of AD, ALS, and FTD brain-derived TDP-43 oligomers (BDT43Os) on tau aggregation using biochemical and biophysical assays. Our results allow us to speculate that TDP-43/tau interactions might play a role in AD, ALS, and FTD. •TDP-43 oligomers occur in AD, ALS and FTD pathologies.•Tau modulates TDP-43 cellular localization and oligomerization.•Brain-derived TDP-43 oligomers can act as seeds for tau oligomerization in vitro.