Complex translational regulation of BACE1 involves upstream AUGs and stimulatory elements within the 5′ untranslated region

BACE1 is the protease responsible for the production of amyloid-beta peptides that accumulate in the brain of Alzheimer's disease ( AD) patients. BACE1 expression is regulated at the transcriptional, as well as post- transcriptional level. Very high BACE1 mRNA levels have been observed in pancreas, but the protein and activity were found mainly in brain. An up-regulation of the protein has been described in some AD patients without a change in transcript levels. The features of BACE1 5' untranslated region (5' UTR), such as the length, GC content, evolutionary conservation and presence of upstream AUGs ( uAUGs), indicate an important regulatory role of this 50 UTR in translational control. We demonstrate that, in brain and pancreas, almost all of the native BACE1 mRNA contains the full-length 50 UTR. RNA transfection and in vitro translation show that translation is mainly inhibited by the presence of the uAUGs. We provide a mutational analysis that highlight the second uAUG as the main inhibitory element while mutations of all four uAUGs fully de- repress translation. Furthermore, we have evidence that a sequence within the region 222- 323 of the BACE1 50 UTR has a stimulatory effect on translation that might depend on the presence of trans- acting factors.