title: Systemic amyloid deposits in familial British dementia.
abstract: Familial British dementia (FBD) is an early onset inherited disorder that, like familial Alzheimer's disease (FAD), is characterized by progressive dementia, amyloid deposition in the brain, and neurofibrillary degeneration of limbic neurons. The primary structure of the amyloid subunit (ABri) extracted from FBD brain tissues (Vidal, R., Frangione, B., Rostagno, A., Mead, S., Revesz, T., Plant, G., and Ghiso, J. (1999) Nature 399, 776-781) is entirely different and unrelated to any previously known amyloid protein. Patients with FBD have a single nucleotide substitution at codon 267 in the BRI2 gene, resulting in an arginine replacing the stop codon and a longer open reading frame of 277 amino acids instead of 266. The ABri peptide comprises the 34 C-terminal residues of the mutated precursor ABriPP-277 and is generated via furin-like proteolytic processing. Here we report that carriers of the Stop-to-Arg mutation have a soluble form of the amyloid peptide (sABri) in the circulation with an estimated concentration in the range of 20 ng/ml, several fold higher than that of soluble Abeta. In addition, ABri species identical to those identified in the brain were also found as fibrillar components of amyloid deposits predominantly in the blood vessels of several peripheral tissues, including pancreas and myocardium. We hypothesize that the high concentration of the soluble de novo created amyloidogenic peptide and/or the insufficient tissue clearance are the main causative factors for the formation of amyloid deposits outside the brain. Thus, FBD constitutes the first documented cerebral amyloidosis associated with neurodegeneration and dementia in which the amyloid deposition is also systemic.
authors.affiliation: Department of Pathology, Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York 10016, USA. ghisoj01@popmail.med.nyu.edu
authors.forename: J A
authors.initials: JA
authors.lastname: Ghiso
authors.forename: J
authors.initials: J
authors.lastname: Holton
authors.forename: L
authors.initials: L
authors.lastname: Miravalle
authors.forename: M
authors.initials: M
authors.lastname: Calero
authors.forename: T
authors.initials: T
authors.lastname: Lashley
authors.forename: R
authors.initials: R
authors.lastname: Vidal
authors.forename: H
authors.initials: H
authors.lastname: Houlden
authors.forename: N
authors.initials: N
authors.lastname: Wood
authors.forename: T A
authors.initials: TA
authors.lastname: Neubert
authors.forename: A
authors.initials: A
authors.lastname: Rostagno
authors.forename: G
authors.initials: G
authors.lastname: Plant
authors.forename: T
authors.initials: T
authors.lastname: Revesz
authors.forename: B
authors.initials: B
authors.lastname: Frangione
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D003704:Dementia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D010446:Peptide Fragments / Q000235:genetics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments