Amyloid and intracellular accumulation of BRI₂

Familial British dementia (FBD) and familial Danish dementia (FDD) are caused by mutations in the BRI₂ gene. These diseases are characterized clinically by progressive dementia and ataxia and neuropathologically by amyloid deposits and neurofibrillary tangles. Herein, we investigate BRI₂ protein accumulation in FBD, FDD, Alzheimer disease and Gerstmann-Sträussler-Scheinker disease. In FBD and FDD, we observed reduced processing of the mutant BRI₂ pro-protein, which was found accumulating intracellularly in the Golgi of neurons and glial cells. In addition, we observed an accumulation of a mature form of BRI₂ protein in dystrophic neurites, surrounding amyloid cores. Accumulation of BRI₂ was also observed in dystrophic neurites of Alzheimer disease and Gerstmann-Sträussler-Scheinker disease cases. Although it remains to be determined whether intracellular accumulation of BRI₂ may lead to cell damage in these degenerative diseases, our study provides new insights into the role of mutant BRI₂ in the pathogenesis of FBD and FDD and implicates BRI₂ as a potential indicator of neuritic damage in diseases characterized by cerebral amyloid deposition.