Spatial patterns of phosphorylation-dependent TDP-43-immunoreactive neuronal cytoplasmic inclusions (NCI) in frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP)

The transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) is an RNA binding protein encoded by the TARDPB gene. Abnormal aggregations of TDP-43 in neurons in the form of neuronal cytoplasmic inclusions (NCI) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of TDP-43 in FTLD-TDP, the spatial patterns of the NCI were studied in frontal and temporal cortex of FTLD-TDP cases using a phosphorylation dependent anti-TDP-43 antibody (pTDP-43). In many regions, the NCI formed clusters and the clusters were distributed regularly parallel to the tissue boundary. In about 35% of cortical regions, cluster size of the NCI was within the size range of the modular columns of the cortex. The spatial patterns of the pTDP-immunoreactive inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody and also similar to inclusions characterized by other molecular pathologies such as tau, ?-synuclein and ‘fused in sarcoma’ (FUS). In conclusion, the data suggest degeneration of cortical and hippocampal anatomical pathways associated with accumulation of cellular pTDP-43 is characteristic of FTLD-TDP. In addition, the data are consistent with the hypothesis of cell to cell transfer of pTDP-43 within the brain.