Amyloid beta 42 peptide (Aβ42)-lowering compounds directly bind to AβE and interfere with amyloid precursor protein (APP) transmembrane dimerization.

Following ectodomain shedding by p-secretase, successive proteolytic cleavages within the transmembrane sequence (TMS) of the amyloid precursor protein (APP) catalyzed by y-secretase result in the release of amyloid-β3 (A13) peptides of variable length. Aβ peptides with 42 amino acids appear to be the key pathogenic species in Alzheimer's disease, as they are believed to initiate neuronal degeneration. Sulindac sulfide, which is known as a potent y-secretase modulator (GSM), selectively reduces Aβ342 production in favor of shorter Aβ species, such as Ap38. By studying APP-TMS dimerization we previously showed that an attenuated interaction similarly decreased Aβ42 levels and concomitantly increased Aβ38 levels. However, the precise molecular mechanism by which GSMs modulate Aβ production is still unclear. In this study, using a reporter gene-based dimerization assay, we found that APP-TMS dimers are destabilized by sulindac sulfide and related A1342-lowering compounds in a concentration-dependent manner. By surface plasmon resonance analysis and NMR spectroscopy, we show that sulindac sulfide and novel sulindac-derived compounds directly bind to the A13 sequence. Strikingly, the attenuated APP-TMS inter- action by GSM5 correlated strongly with AI342-lowering activity and binding strength to the Aβ sequence. Molecular docking analyses suggest that certain GSMs bind to the GxxxG dimerization motif in the APP-TMS. We conclude that these GSMs decrease Aβ42 levels by modulating APP-TMS interactions. This effect specifically emphasizes the importance of the dimeric APP-TMS as a promising drug target in Alzheimer's disease. [ABSTRACT FROM AUTHOR]