Detection of TDP‐43 oligomers in frontotemporal lobar degeneration–TDP
Copyright policy )Detection of TDP‐43 oligomers in frontotemporal lobar degeneration–TDP
ObjectiveThe 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.MethodsPostmortem 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.ResultsTDP‐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.InterpretationTDP‐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
- University of California, San Francisco United States
- University of California, Davis United States
- Genomics Research Center, Academia Sinica Taiwan
- University Memory and Aging Center United States
- Academia Sinica Taiwan
Male, Aging, DNA-Binding Proteins (mesh), Amyloid (mesh), Neurodegenerative, Acquired Cognitive Impairment (rcdc), Hippocampus, Aging (rcdc), Biopolymers, Brain Disorders (rcdc), 1103 Clinical Sciences (for), Dementia (rcdc), 2.1 Biological and endogenous factors, Neurology & Neurosurgery (science-metrix), 32 Biomedical and Clinical Sciences (for-2020), Male (mesh), Alzheimer's Disease Related Dementias (ADRD), Neurosciences (rcdc), Neurodegenerative (rcdc), Neurons, Humans (mesh), Microscopy, Prefrontal Cortex (mesh), Middle Aged, Biopolymers (mesh), 3209 Neurosciences (for-2020), Immunohistochemistry, Alzheimer's Disease Related Dementias (ADRD) (rcdc), DNA-Binding Proteins, Frontotemporal Dementia (FTD), Frontotemporal Dementia (FTD) (rcdc), Neurological, Female, Amyloid, Clinical Sciences, Immunohistochemistry (mesh), 610, Prefrontal Cortex, Electron, Rare Diseases (rcdc), Rare Diseases, Middle Aged (mesh), Acquired Cognitive Impairment, Humans, Frontotemporal Lobar Degeneration (mesh), 3202 Clinical Sciences (for-2020), Aged, Neurology & Neurosurgery, Neurons (mesh), Sclerosis, Biomedical and Clinical Sciences, Neurological (hrcs-hc), Aged (mesh), Amyotrophic Lateral Sclerosis, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors (hrcs-rac), 3202 Clinical sciences (for-2020), Electron (mesh), 1109 Neurosciences (for), Brain Disorders, Amyotrophic Lateral Sclerosis (mesh), Microscopy, Electron, Sclerosis (mesh), Female (mesh), Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) (rcdc), Frontotemporal Lobar Degeneration, Hippocampus (mesh)
Male, Aging, DNA-Binding Proteins (mesh), Amyloid (mesh), Neurodegenerative, Acquired Cognitive Impairment (rcdc), Hippocampus, Aging (rcdc), Biopolymers, Brain Disorders (rcdc), 1103 Clinical Sciences (for), Dementia (rcdc), 2.1 Biological and endogenous factors, Neurology & Neurosurgery (science-metrix), 32 Biomedical and Clinical Sciences (for-2020), Male (mesh), Alzheimer's Disease Related Dementias (ADRD), Neurosciences (rcdc), Neurodegenerative (rcdc), Neurons, Humans (mesh), Microscopy, Prefrontal Cortex (mesh), Middle Aged, Biopolymers (mesh), 3209 Neurosciences (for-2020), Immunohistochemistry, Alzheimer's Disease Related Dementias (ADRD) (rcdc), DNA-Binding Proteins, Frontotemporal Dementia (FTD), Frontotemporal Dementia (FTD) (rcdc), Neurological, Female, Amyloid, Clinical Sciences, Immunohistochemistry (mesh), 610, Prefrontal Cortex, Electron, Rare Diseases (rcdc), Rare Diseases, Middle Aged (mesh), Acquired Cognitive Impairment, Humans, Frontotemporal Lobar Degeneration (mesh), 3202 Clinical Sciences (for-2020), Aged, Neurology & Neurosurgery, Neurons (mesh), Sclerosis, Biomedical and Clinical Sciences, Neurological (hrcs-hc), Aged (mesh), Amyotrophic Lateral Sclerosis, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors (hrcs-rac), 3202 Clinical sciences (for-2020), Electron (mesh), 1109 Neurosciences (for), Brain Disorders, Amyotrophic Lateral Sclerosis (mesh), Microscopy, Electron, Sclerosis (mesh), Female (mesh), Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) (rcdc), Frontotemporal Lobar Degeneration, Hippocampus (mesh)
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