Detection of TDP‐43 oligomers in frontotemporal lobar degeneration–TDP

Objective The proteinaceous inclusions in TDP‐43 proteinopathies such as frontotemporal lobar degeneration (FTLD)‐TDP are made of high–molecular‐weight aggregates of TDP‐43. These aggregates have not been classified as amyloids, as prior amyloid staining results were not conclusive. Here we used a specific TDP‐43 amyloid oligomer antibody called TDP‐O to determine the presence and abundance of TDP‐43 oligomers among different subtypes of FTLD‐TDP as well as in hippocampal sclerosis (HS), which represents a non‐FTLD pathology with TDP‐43 inclusions. Methods Postmortem tissue from the hippocampus and anterior orbital gyrus from 54 prospectively assessed and diagnosed subjects was used for immunostaining with TDP‐O. Electron microscopy was used to assess the subcellular locations of TDP‐O–decorated structures. Results TDP‐43 inclusions staining with TDP‐O were present in FTLD‐TDP and were most conspicuous for FTLD‐TDP type C, the subtype seen in most patients with semantic variant primary progressive aphasia. TDP‐O immunoreactivity was absent in the hippocampus of HS patients despite abundant TDP‐43 inclusions. Ultrastructurally, TDP‐43 oligomers resided in granular or tubular structures, frequently in close proximity to, but not within, neuronal lysosomes. Interpretation TDP‐43 forms amyloid oligomers in the human brain, which may cause neurotoxicity in a manner similar to other amyloid oligomers. Oligomer formation may contribute to the conformational heterogeneity of TDP‐43 aggregates and mark the different properties of TDP‐43 inclusions between FTLD‐TDP and HS. Ann Neurol 2015;78:211–221