title: Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia.
abstract: Familial British dementia (FBD), pathologically characterized by cerebral amyloid angiopathy (CAA), amyloid plaques, and neurofibrillary degeneration, is associated with a stop codon mutation in the BRI gene resulting in the production of an amyloidogenic fragment, amyloid-Bri (ABri). The aim of this study was to assess the distribution of ABri fibrillar and nonfibrillar lesions and their relationship to neurofibrillary pathology, astroglial and microglial response using immunohistochemistry, confocal microscopy, and immunoelectron microscopy in five cases of FBD. Abnormal tau was studied with immunoblotting. We present evidence that ABri is deposited throughout the central nervous system in blood vessels and parenchyma where both amyloid (fibrillar) and pre-amyloid (nonfibrillar) lesions are formed. Ultrastructurally amyloid lesions appear as bundles of fibrils recognized by an antibody raised against ABri, whereas Thioflavin S-negative diffuse deposits consist of amorphous electron-dense material with sparse, dispersed fibrils. In contrast to nonfibrillar lesions, fibrillar ABri is associated with a marked astrocytic and microglial response. Neurofibrillary tangles and neuropil threads occurring mainly in limbic structures, are found in areas affected by all types of ABri lesions whereas abnormal neurites are present around amyloid lesions. Immunoblotting for tau revealed a triplet electrophoretic migration pattern. Our observations confirm a close link between ABri deposition and neurodegeneration in FBD.
authors.affiliation: Department of Neuropathology, Institute of Neurology, University College London, London, United Kingdom.
authors.forename: J L
authors.initials: JL
authors.lastname: Holton
authors.forename: J
authors.initials: J
authors.lastname: Ghiso
authors.forename: T
authors.initials: T
authors.lastname: Lashley
authors.forename: A
authors.initials: A
authors.lastname: Rostagno
authors.forename: C J
authors.initials: CJ
authors.lastname: Guerin
authors.forename: G
authors.initials: G
authors.lastname: Gibb
authors.forename: H
authors.initials: H
authors.lastname: Houlden
authors.forename: H
authors.initials: H
authors.lastname: Ayling
authors.forename: L
authors.initials: L
authors.lastname: Martinian
authors.forename: B H
authors.initials: BH
authors.lastname: Anderton
authors.forename: N W
authors.initials: NW
authors.lastname: Wood
authors.forename: R
authors.initials: R
authors.lastname: Vidal
authors.forename: G
authors.initials: G
authors.lastname: Plant
authors.forename: B
authors.initials: B
authors.lastname: Frangione
authors.forename: T
authors.initials: T
authors.lastname: Revesz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid / Q000276:immunology / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000032:analysis / Q000276:immunology; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D052160:Benzothiazoles; D001808:Blood Vessels / Q000737:chemistry / Q000473:pathology; D002490:Central Nervous System / Q000737:chemistry* / Q000473:pathology / Q000648:ultrastructure; D003224:Congo Red; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D020271:Heredodegenerative Disorders, Nervous System / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry / Q000379:methods; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016253:Microscopy, Immunoelectron; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D013194:Staining and Labeling / Q000379:methods; D013844:Thiazoles; D016875:tau Proteins / Q000032:analysis; D000097382:CD68 Molecule
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D052160:Benzothiazoles; D003224:Congo Red; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D013844:Thiazoles; D016875:tau Proteins; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C120083:ITM2B protein, human; C009462:thioflavin T