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Ann Neurol. 2015 Aug;78(2):211-21. doi: 10.1002/ana.24431. Epub 2015 Jun 30.

Detection of TDP-43 oligomers in frontotemporal lobar degeneration-TDP.

Author information

1
Department of Pathology and Laboratory Medicine, University of California, Davis, School of Medicine, Sacramento, CA.
2
Alzheimer's Disease Center, University of California, Davis, School of Medicine, Sacramento, CA.
3
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
4
Department of Neurology, University of California, Davis, School of Medicine, Sacramento, CA.
5
Departments of Neurology and Pathology, University of California, San Francisco, San Francisco, CA.

Abstract

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.

PMID:
25921485
PMCID:
PMC4822421
DOI:
10.1002/ana.24431
[Indexed for MEDLINE]
Free PMC Article

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