BRI2, a protein mutated in Familial British and Familial Danish Dementias, interacts with Amyloid Precursor
Protein (APP) and reduces the levels of secreted APPβ (sAPPβ), which derives from APP cleavage by β-secretase
(BACE1). Exploring the mechanisms of this effect, we obtained data that BRI2 decreases the cellular levels of BACE1
thus reducing the β-cleavage of APP. Deletion of N-terminal cytoplasmic or C-terminal extracellular sequences of BRI2
neither affected its interaction with BACE1 or APP (Fotinopoulou et al., 2005) nor the reduction in the levels of BACE1
and sAPPβ. These results suggest that BRI2 may prevent access of BACE1 to APP and the BRI2/BACE1 interaction may
mediate the reduction in BACE1 levels. In support, BRI2 expression induced lysosomal but not proteasomal degradation
of BACE1. In parallel, BRI2 expression was also found to reduce BACE1 mRNA levels by 50%. This study adds novel
information regarding the mechanism by which BRI2 affects APP processing and BACE1 levels.
Keywords: Familial British dementia, Familia Danish dementia, Alzheimer’s disease, neurodegeneration, BRI2, APP, BACE1.
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