title: TDP-43 pathology in familial British dementia.
abstract: 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.
authors.affiliation: Department of Psychiatry, Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T1Z3, Canada. cschwab@cmmt.ubc.ca
authors.forename: Claudia
authors.initials: C
authors.lastname: Schwab
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Arai
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Sheng
authors.initials: S
authors.lastname: Yu
authors.forename: Patrick L
authors.initials: PL
authors.lastname: McGeer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003704:Dementia / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008032:Limbic System / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D016875:tau Proteins