An NSAID-like Compound, FT-9, Preferentially Inhibits γ-Secretase Cleavage of the Amyloid Precursor Protein Compared to Its Effect on Amyloid Precursor-like Protein

摘要

Inhibition of γ-secretase cleavage of the amyloid precursor protein (APP) is a prime target for thendevelopment of therapeutics for treating Alzheimer’s disease; however, complete inhibition of this activitynwould also impair the processing of many other proteins, including the APP homologues, amyloid precursor-nlike protein (APLP) 1 and 2. To prevent unwanted side effects, therapeutically useful γ-secretase inhibitorsnshould specifically targetAPP processing while sparing cleavage of other γ-substrates. Thus, sinceAPLP1 andnAPLP2 are more similar to APP than any of the other known γ-secretase substrates and have importantnphysiological roles in their own right, we reasoned that comparison of the effect of γ-secretase inhibitors onnAPLP processing should provide a sensitive indicator of the selectivity of putative inhibitors. To address thisnissue, we have optimized microsome and cell culture assays to monitor the γ-secretase proteolysis of APP andnAPLPs. Production of the γ-secretase-generated intracellular domain (ICD) occurs more rapidly fromnAPLP1 than from either APLP2 or APP, suggesting that APLP1 is a better γ-substrate and that substratenrecognition is not restricted to the highly conserved amino acid sequences surrounding the ε-site. As expected,nthe well-characterized γ-secretase modulator, fenofibrate, did not inhibit ICD release, whereas a relatedncompound, FT-9, inhibited γ-secretase both in microsomes and in whole cells. Importantly, FT-9 displayed anpreferential effect, inhibiting cleavage of APP much more effectively than cleavage of APLP1. These findingsnsuggest that selective inhibitors can be developed and that screening of compounds against APP and APLPsnshould assist in this process.