Systemic Amyloid Deposits in Familial British Dementia*

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 Aβ. 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 solublede 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.

[1]  R. Bateman,et al.  Steady-state kinetics of glutamine cyclotransferase. , 1994, Archives of biochemistry and biophysics.

[2]  S. Mead,et al.  Familial British dementia with amyloid angiopathy: early clinical, neuropsychological and imaging findings. , 2000, Brain : a journal of neurology.

[3]  Agueda Rostagno,et al.  A stop-codon mutation in the BRI gene associated with familial British dementia , 1999, Nature.

[4]  C. Patlak,et al.  Fate of Cerebrospinal Fluid‐Borne Amyloid β‐Peptide: Rapid Clearance into Blood and Appreciable Accumulation by Cerebral Arteries , 1996, Journal of neurochemistry.

[5]  E. Matsubara,et al.  Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Jon Thorgeir Hallgrimsson,et al.  HEREDITARY CEREBRAL HEMORRHAGE WITH AMYLOIDOSIS , 1972 .

[7]  T Bek,et al.  A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[8]  C. Masters,et al.  The familial occurrence of Creutzfeldt-Jakob disease and Alzheimer's disease. , 1981, Brain : a journal of neurology.

[9]  B. Frangione,et al.  Non-Alzheimer's disease amyloidoses of the nervous system. , 1995, Current opinion in neurology.

[10]  D. Dickson,et al.  Neurodegenerative diseases with cytoskeletal pathology: A biochemical classification , 1997, Annals of neurology.

[11]  S. Love,et al.  Familial cerebellar ataxia with cerebrovascular amyloid , 1982, Journal of neurology, neurosurgery, and psychiatry.

[12]  J. Sweedler,et al.  Formation of N‐Pyroglutamyl Peptides from N‐Glu and N‐Gln Precursors in Aplysia Neurons , 1999, Journal of neurochemistry.

[13]  Neil D. Rawlings,et al.  Handbook of proteolytic enzymes , 1998 .

[14]  D. Steiner,et al.  Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia , 1999, Nature Neuroscience.

[15]  J. Holton,et al.  Amyloidogenesis in Familial British Dementia Is Associated with a Genetic Defect on Chromosome 13 , 2000, Annals of the New York Academy of Sciences.

[16]  L. Martinian,et al.  Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia. , 2001, The American journal of pathology.

[17]  T. Mandybur,et al.  Atypical Gerstmann‐Straüssler syndrome or familial spinocerebellar ataxia and Alzheimer's disease? , 1987, Neurology.

[18]  K. Pittois,et al.  cDNA sequence analysis, chromosomal assignment and expression pattern of the gene coding for integral membrane protein 2B. , 1998, Gene.

[19]  D. Oppenheimer,et al.  Congophilic angiopathy of the brain: a clinical and pathological report on two siblings. , 1982, Journal of neurology, neurosurgery, and psychiatry.

[20]  J. Holton,et al.  Cytoskeletal pathology in familial cerebral amyloid angiopathy (British type) with non-neuritic amyloid plaque formation , 1999, Acta Neuropathologica.

[21]  J. Ghiso,et al.  Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C). , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[22]  G. Plant,et al.  Familial cerebral amyloid angiopathy with nonneuritic amyloid plaque formation. , 1990, Brain : a journal of neurology.

[23]  C. Worster-Drought,et al.  Familial Presenile Dementia with Spastic Paralysis* , 1933, The Journal of neurology and psychopathology.

[24]  H. Vinters Cerebral amyloid angiopathy. A critical review. , 1987, Stroke.

[25]  D. Holtzman,et al.  Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. , 2000, The Journal of clinical investigation.

[26]  A. Bateman,et al.  Post-translational modification of bovine pro-opiomelanocortin. Tyrosine sulfation and pyroglutamate formation, a mass spectrometric study. , 1990, The Journal of biological chemistry.

[27]  Kinuko Suzuki,et al.  Atypical Alzheimer's disease with spastic paresis and ataxia , 1985, Annals of neurology.

[28]  D. Selkoe,et al.  Mass spectrometry of purified amyloid beta protein in Alzheimer's disease. , 1992, The Journal of biological chemistry.

[29]  D. Selkoe,et al.  Amyloid β-protein deposition in tissues other than brain in Alzheimer's disease , 1989, Nature.

[30]  D. Yew Cell kinetic in retinal cell morphogenesis , 1979, Neuroscience Letters.

[31]  The genetics of neurological disorders , 1982 .

[32]  Molecular genetics of Alzheimer’s disease , 2000, Biological Psychiatry.

[33]  W. Busby,et al.  An enzyme(s) that converts glutaminyl-peptides into pyroglutamyl-peptides. Presence in pituitary, brain, adrenal medulla, and lymphocytes. , 1987, The Journal of biological chemistry.

[34]  W. Markesbery,et al.  N‐terminal Heterogeneity of Parenchymal and Cerebrovascular Aβ Deposits , 1998, Journal of neuropathology and experimental neurology.