Familial British dementia: colocalization of furin and ABri amyloid.
Familial British dementia (FBD) is an autosomal dominant condition caused by a point mutation in the stop codon of the BRI gene. This mutation extends the normal precursor protein (PP) of 266 amino acids to the next stop codon, which is at amino acid 277. Kim and colleagues demonstrated in vitro that furin can process both the normal protein BriPP and the extended protein ABriPP to produce C-terminal fragments of 23 and 34 amino acids. The abnormal C-terminal fragment, ABri, accumulates in FBD in the form of extracellular amyloid deposits. The objective of our study was to determine if furin is associated with ABri in FBD. Brain tissue of one case of FBD, four cases of Alzheimer's disease (AD) and two controls were studied by immunohistochemistry using antibodies against furin, beta-amyloid protein and ABri. In FBD, furin was found to be colocalized with ABri deposits and amyloid angiopathy in all areas examined. In contrast beta-amyloid deposits in AD were not immunostained by the furin antibody. In normal as well as pathological cases, clusters of neurons in the hippocampus and neocortex showed light to moderate furin immunostaining, while peptidergic neurons of the hypothalamus showed intense furin-immunostaining. These data suggest that furin may be involved in producing the pathological fragment of ABriPP in vivo and that inhibition of furin might be a method of treating this disorder.
Schwab
Claudia
C
Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. cschwab@interchange.ubc.ca
Hosokawa
Masato
M
Akiyama
Haruhiko
H
McGeer
Patrick L
PL
D000368:Aged; D000369:Aged, 80 and over; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D003704:Dementia / Q000378:metabolism* / Q000473:pathology; D005260:Female; D045683:Furin / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism
D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D045683:Furin