Age-dependent changes in TDP-43 levels in a mouse model of Alzheimer disease are linked to A oligomers accumulation

Background. Transactive response DNA-binding protein 43 (TDP-43) is the pathological protein found in frontotemporal lobar degeneration with ubiquitin positive inclusions and in amyotrophic lateral sclerosis. In diseased tissue, TDP-43 translocates from its physiological nuclear location into the cytoplasm, where it accumulates. Additionally, C-terminal fragments of TDP-43 accumulate in affected brain regions and are sufficient to cause TDP-43 mislocalization and cytoplasmic accumulation in vitro. TDP-43 also accumulates in 30% of Alzheimer disease (AD) cases, a finding that has been highly reproducible. The role of TDP-43 in AD and its relation with A and tau pathology, the two neuropathological hallmarks of AD, remains to be elucidated. Results. Here we show that levels of TDP-43 and its ∼35 kDa C-terminal fragment are significantly increased in the 3×Tg-AD mice, an animal model of AD that develops an age-dependent cognitive decline linked to the accumulation of A and tau. We also report that the levels of TDP-43 and its C-terminal fragment correlate with the levels of soluble A oligomers, which play a key role in AD pathogenesis. Notably, genetically reducing A₄₂production restores the levels of TDP-43 and its ∼35 kDa C-terminal fragment to control levels. Conclusions. These data suggest a possible relation between A oligomers and TDP-43.