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- W2085152154 abstract "NSAIDs (Non-steroidal anti-inflammatory drugs) were found to decrease the risk of developing Alzheimer Disease (AD) and to modulate the generation of Amyloid-ß (Aß) peptide species on a molecular level. Subgroups of NSAIDs were shown to either decrease Aß42 levels and to increase Aß38 levels or vice versa, thus acting as γ-secretase modulators (GSM). Thereby, a reduction of Aß42 levels is beneficial, as especially the Aß42 isoform appears to be the key pathogenic species. However, the exact molecular mechanism of Aß42 modulation by NSAIDs is unclear. We have previously identified the GxxxG interaction motif in the transmembrane sequence (TMS) of APP, which enables the homophilic dimerization of the APP-TMS (Munter et al, 2007). According to our data, dimerization of the APP-TMS promotes the generation of Aß42 in favor of Aß38 levels, whereas a reduced dimerization works vice versa. As NSAIDs and GxxxG mutations were reported to modulate Aß production in a similar way, we tested if NSAIDs can also affect the APP-TMS dimer. To investigate the influence of NSAIDs on APP-TMS dimerization by direct binding and a bacterial test system. Using the bacterial reporter gene-based ToxR assay the stability of TMS dimerization can be quantified in the presence and absence of diverse compounds. We found that the helix-helix interaction of the APP-TMS is attenuated in a concentration-dependent manner by sulindac sulfide and indomethacin, but not by sulindac sulfone. In addition, specific binding of only dimer-affecting NSAIDs to the Aß sequence was observed by Surface Plasmon Resonance (SPR). Taken together, both sulindac sulfide and indomethacin which are known to reduce Aß42 levels revealed a functional link between APP-TMS dimerization and Aß42 generation. Our data strongly suggest that a subgroup of NSAIDs can modulate Aß generation due to an inhibition of helix-helix interactions of membrane spanning Aß segments. Together with our previous observations, this strongly indicates that the dimeric TMS of APP represents an ideal drug target." @default.
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- W2085152154 date "2009-07-01" @default.
- W2085152154 modified "2023-09-26" @default.
- W2085152154 title "P3-203: Nsaids modulate app dimerization" @default.
- W2085152154 doi "https://doi.org/10.1016/j.jalz.2009.04.976" @default.
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