Anti-amyloidogenic processing of the amyloid precursor protein APP by 
α-secretase prevents formation of the amyloid-β peptide, which accumulates in 
senile plaques of Alzheimer disease patients. α-Secretase belongs to the family 
of a disintegrin and metalloproteases (ADAMs), and ADAM10 is the primary 
candidate for this anti-amyloidogenic activity. We recently demonstrated that 
ADAM10 translation is repressed by its 5'-UTR and that in particular the first 
half of ADAM10 5'-UTR is responsible for translational repression. Here, we 
asked whether specific sequence motifs exist in the ADAM10 5'-UTR that are able 
to form complex secondary structures and thus potentially inhibit ADAM10 
translation. Using circular dichroism spectroscopy, we demonstrate that a G-rich 
region between nucleotides 66 and 94 of the ADAM10 5'-UTR forms a highly stable, 
intramolecular, parallel G-quadruplex secondary structure under physiological 
conditions. Mutation of guanines in this sequence abrogates the formation of the 
G-quadruplex structure. Although the G-quadruplex structure efficiently inhibits 
translation of a luciferase reporter in in vitro translation assays and in 
living cells, inhibition of G-quadruplex formation fails to do so. Moreover, 
expression of ADAM10 was similarly repressed by the G-quadruplex. Mutation of 
the G-quadruplex motif results in a significant increase of ADAM10 levels and 
consequently APPsα secretion. Thus, we identified a critical RNA secondary 
structure within the 5'-UTR, which contributes to the translational repression 
of ADAM10.