Abstract
Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease caused by a 10-nucleotide duplication-insertion in the BRI2 gene. FDD is clinically characterized by loss of vision, hearing impairment, cerebellar ataxia and dementia. The main neuropathologic findings in FDD are the deposition of Danish amyloid (ADan) and the presence of neurofibrillary tangles (NFTs). Here we investigated tau accumulation and truncation in double transgenic (Tg-FDD-Tau) mice generated by crossing transgenic mice expressing human Danish mutant BRI2 (Tg-FDD) with mice expressing human 4-repeat mutant Tau-P301S (Tg-Tau). Compared to Tg-Tau mice, we observed a significant enhancement of tau deposition in Tg-FDD-Tau mice. In addition, a significant increase in tau cleaved at aspartic acid (Asp) 421 was observed in Tg-FDD-Tau mice. Tg-FDD-Tau mice also showed a significant decrease in synaptophysin levels, occurring before widespread deposition of fibrillar ADan and tau can be observed. Thus, the presence of soluble ADan/mutant BRI2 can lead to significant changes in tau metabolism and synaptic dysfunction. Our data provide new in vivo insights into the pathogenesis of FDD and the pathogenic pathway(s) by which amyloidogenic peptides, regardless of their primary amino acid sequence, can cause neurodegeneration.
Highlights
Two early-onset autosomal dominant diseases known as familial British dementia (FBD) and familial Danish dementia (FDD) are caused by mutations in the BRI2 gene [1,2,3,4]
Additional rotarod analysis in older mice was not performed because the decline in motor performance that led to a reduced survival rate in Tg-Tau mice beginning around 9 months of age was observed in Tg-FDD-Tau mice
Tg-FDD-Tau mice exhibited an age-dependent accumulation of both are the deposition of Danish amyloid (ADan) and tau; the results of this study show that expression of human mutant BRI2 enhances tau phosphorylation and C-terminal cleavage of neuronal tau, while ADan deposition remained comparable to its parental strain
Summary
Two early-onset autosomal dominant diseases known as familial British dementia (FBD) and familial Danish dementia (FDD) are caused by mutations in the BRI2 gene [1,2,3,4]. Cleavage of the BRI2 protein within its ectodomain (residue Arg243 and Glu244, KGIQKRQEAS) by pro-protein convertases (PCs) [7,8,9] releases a 23 amino acid pro-peptide from the wildtype precursor protein and 34 amino acid long amyloid peptides in patients with FBD (ABri) and FDD (ADan) [3,4]. The remaining membrane associated N-terminal fragment (NTF) undergoes intramembrane proteolysis mediated by SPPL2a or SPPL2b. This cleavage generates an intracellular domain, which is liberated into the cytosol and a secreted C domain [10,11,12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
