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

Mauro Montalbano, Salome McAllen, Filippa Lo Cascio, Urmi Sengupta, Stephanie Garcia, Nemil Bhatt, Anna Ellsworth, Eric A. Heidelman, Omar D. Johnson, Samantha Doskocil, Rakez Kayed

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number105130
JournalNeurobiology of Disease
Volume146
DOIs
StatePublished - Dec 2020

Keywords

  • Aggregation
  • Neurodegeneration
  • Oligomer
  • TDP-43
  • Tau
  • Tauopathies

ASJC Scopus subject areas

  • Neurology

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