RNA interference silencing of DRAL affects processing of amyloid precursor protein

Abstract

In a previous study, we reported that Alzheimer's disease-associated presenilin-2 interacts with a LIM-domain protein, namely, DRAL/FHL2/SLIM3. In this study, we investigated whether DRAL modifies the metabolism of the amyloid precursor protein (APP). We used small interfering RNA (siRNA) to knockdown DRAL in COS7 and HEK293 cells that stably overexpress APP695. We found that the knockdown was accompanied by a decrease in the amount of secreted alpha-secretase-cleaved APP and the membrane-bound C-terminal fragment C83 and an increase in the amount of secreted beta-amyloid peptide (Abeta) from the cells. We also found that in addition to a disintegrin and metalloprotease (ADAM)-17, DRAL binds to ADAM-10. Thus, DRAL may be involved in the processing of APP through the alpha-secretase pathway.