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J. Biol. Chem., Vol. 276, Issue 47, 43909-43914, November 23, 2001

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Systemic Amyloid Deposits in Familial British Dementia^*

Jorge A. Ghiso^§¶, Janice Holton^§§, Leticia Miravalle, Miguel Calero, Tammaryn Lashley^§§, Ruben Vidal, Henry Houlden^§§, Nicholas Wood^§§, Thomas A. Neubert^**, Agueda Rostagno, Gordon Plant, Tamas Révész^§§, and Blas Frangione^§

From the  Departments of Pathology, ^§ Psychiatry, and ^** Pharmacology and Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016 and the  Division of Neuropathology and ^§§ Department of Molecular Pathogenesis, Institute of Neurology and  National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, United Kingdom

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 A. 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.

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