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.