Journal
ACTA NEUROPATHOLOGICA
Volume 118, Issue 2, Pages 303-311Publisher
SPRINGER
DOI: 10.1007/s00401-009-0514-3
Keywords
TDP-43; Familial British dementia; ABri; Ubiquitin; Intracellular inclusions; Phosphorylation-dependent TDP-43 antibodies
Categories
Funding
- Pacific Alzheimer Research Foundation
- Grants-in-Aid for Scientific Research [21591536] Funding Source: KAKEN
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Trans-activation-responsive DNA-binding protein 43 (TDP-43) is a component of pathological inclusions in amyotrophic lateral sclerosis and several forms of sporadic and familial frontotemporal lobar degeneration. This has suggested defining a new class of diseases known as TDP-43 proteinopathies. However, it has been reported more recently that TDP-43 positive inclusions occur in other neurodegenerative disorders such as Alzheimer's disease, Dementia with Lewy Bodies and Parkinsonism dementia complex of Guam. Here we report the occurrence of TDP-43 inclusions in one other neurodegenerative disorder: familial British dementia. Using a variety of antibodies against phosphorylated and non-phosphorylated TDP-43 epitopes, we found intense accumulation occurred in the form of dystrophic neurites, neuronal cytoplasmic inclusions and was also occasionally associated with neurofibrillary tangles. Double immunostaining revealed that TDP-43 and tau aggregates were rarely directly colocalized, but co-existed in the same neurons as separate inclusions. Double staining with ubiquitin showed a direct colocalization with TDP-43. The phosphorylation-dependent TDP-43 antibodies proved superior to phosphorylation-independent antibodies in revealing pathological inclusions since the former did not stain non-phosphorylated TDP-43 in normal nuclei. Our results support the concept that TDP-43 pathology is not narrowly restricted, but is involved in the etiology of many neurodegenerative disorders.
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