Generation and Initial Characterization of FDD Knock In Mice

Background: Mutations in the integral membrane protein 2B [1], also known as BRI2 [2], a type II trans-membrane domain protein cause two autosomal dominant neurodegenerative diseases, Familial British and Danish Dementia [3]. In these conditions, accumulation of a C-terminal peptide (ABri and ADan) cleaved off from the mutated precursor protein by the pro-protein convertase furin [4], leads to amyloid deposition in the walls of blood vessels and parenchyma of the brain. Recent advances in the understanding of the generation of amyloid in Alzheimer's disease has lead to the finding that BRI2 interacts with the Amyloid Precursor Protein (APP), decreasing the efficiency of APP processing to generate A beta [5,6,7]. The interaction between the two precursors, APP and BRI2, and possibly between A beta and ABri or ADan, could be important in influencing the rate of amyloid production or the tendency of these peptides to aggregate. Methodology/Principal Findings: We have generated the first BRI2 Danish Knock-In (FDDKI) murine model of FDD, expressing the pathogenic decamer duplication in exon 6 of the BRI2 gene. FDDKI mice do not show any evident abnormal phenotype, with normal brain histology and no detectable amyloid deposition in blood vessel walls or parenchyma. Conclusions/Significance: This new murine mouse model will be important to further understand the interaction between APP and BRI2, and to provide insights into the molecular basis of FDD.