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.


CONCLUSIONS
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.
Department of Pathology and Laboratory Medicine, University of California, Davis, School of Medicine, Sacramento, CA.|Alzheimer's Disease Center, University of California, Davis, School of Medicine, Sacramento, CA.
Patricia F
PF
Kao
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Yun-Ru
YR
Chen
Department of Pathology and Laboratory Medicine, University of California, Davis, School of Medicine, Sacramento, CA.
Xiao-Bo
XB
Liu
Alzheimer's Disease Center, University of California, Davis, School of Medicine, Sacramento, CA.|Department of Neurology, University of California, Davis, School of Medicine, Sacramento, CA.
Charles
C
DeCarli
Departments of Neurology and Pathology, University of California, San Francisco, San Francisco, CA.
William W
WW
Seeley
Department of Pathology and Laboratory Medicine, University of California, Davis, School of Medicine, Sacramento, CA.|Alzheimer's Disease Center, University of California, Davis, School of Medicine, Sacramento, CA.
Lee-Way
LW
Jin
D000368:Aged; D000682:Amyloid / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D001704:Biopolymers / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000648:ultrastructure; D012598:Sclerosis
D000682:Amyloid; D001704:Biopolymers; D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human