Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia

Familial British dementia (FBD), pathologically characterized by cerebral a myloid 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 thi s study was to assess the distribution of ABri fibrillar and nonfibrillar l esions acid their relationship to neurofibrillary pathology, astroglial and microglial response using immunohistochemistry, confocal microscopy, and i mmunoelectron microscopy in five cases of FED. Abnormal tau was studied wit h immunoblotting. We present evidence that ABri is deposited throughout the central nervous system in blood vessels and parenchyma where both amyloid (fibrillar) and preamyloid (nonfibrillar) lesions are formed. Ultrastructur ally amyloid lesions appear as bundles of fibrils recognized by an antibody raised against ABri, whereas Thioflavin S-negative diffuse deposits consis t of amorphous electron-dense material with sparse, dispersed fibrils. In c ontrast to nonfibrillar lesions, fibrillar ABri is associated with a marked astrocytic and microglial response. Neurofibrillary tangles and neuropil t hreads occurring mainly in limbic structures, are found in areas affected b y all types of ABri lesions whereas abnormal neurites are present around am yloid lesions, Immunoblotting for tau revealed a triplet electrophoretic mi gration pattern. Our observations confirm a close link between ABri deposit ion and neurodegeneration in FED.