Expression of the Alzheimer protease BACE1 is suppressed via its 5′-untranslated region

The aspartyl protease BACE1 has a pivotal role in the pathogenesis of Alzheimer's disease. Recently, it was shown that in Alzheimer's disease patients, BACE1 levels were elevated although mRNA levels were not changed compared with controls. Here, we demonstrate that the 5'-untranslated region (5' UTR) of BACE1 controls the rate of BACE1 translation. In the presence of the 5' UTR, we observed more than 90% reduction of BACE1 protein levels in HEK293, COS7 and H4 cells, and a similar reduction of BACE1 activity in vitro. mRNA levels were not affected, demonstrating that the 5' UTR repressed the translation but not the transcription of BACE1. The 3' UTR did not affect BACE1 expression. An extensive mutagenesis analysis predicts that the GC-rich region of the 5' UTR forms a constitutive translation barrier, which may prevent the ribosome from efficiently translating the BACE1 mRNA. Our data therefore demonstrate translational repression as a new mechanism controlling BACE1 expression.