Caspase-cleaved TAR DNA-binding protein-43 in Pick's disease.

The hyperphosphorylation and proteolytic modification of the TAR DNA binding protein-43 (TDP-43) is a key finding in a number of neurodegenerative diseases including frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U), amyotrophic lateral sclerosis (ALS), and most recently Alzheimer's disease (AD). To examine whether proteolytic modifications of TDP-43 is a relevant finding in Pick's disease, we utilized a novel site-directed caspase-cleavage antibody based upon a known caspase-3 cleavage consensus site within TDP-43 at position 219. Application of this antibody, termed TDP caspase-cleavage product (TDPccp) to postmortem Pick's disease brain sections revealed the presence of caspase-cleaved TDP-43 in Pick and Hirano bodies predominantly within region CA1 of the hippocampus. Co-localization of TDPccp with PHF-1, a general marker for Pick bodies, as well as with an antibody to caspase-cleaved tau (TauC3) was evident within the hippocampus. A semi-quantitative analysis indicated that approximately 21% and 79% of the Pick bodies identified in area CA1 contained caspase-cleaved TDP-43 or caspase-cleaved tau, respectively. Of interest was the lack of co-localization of TDPccp with PHF-1 in Pick bodies within the dentate gyrus. Collectively, these data have identified modified TDP-43 as a component of Pick and Hirano bodies that is restricted to area CA1 in Pick's disease. The relative paucity of caspase-cleaved TDP-43 found within Pick bodies in comparison to caspase-cleaved tau suggests that TDP-43 and its modification by caspases is most likely not a contributing factor leading to Pick body formation.