A natural squamosamide derivative FLZ reduces amyloid-beta production by increasing non-amyloidogenic AbetaPP processing.

Substantial evidence supports a central role of Abeta in the pathogenesis of Alzheimer's disease (AD). We have demonstrated that FLZ, a synthetic cyclic analogue of natural squamosamide, exhibits neuroprotective actions in cells and mouse models, suggesting future investigation of FLZ as a candidate compound for the treatment of AD. In this study, we found that the production of amyloid-beta (Abeta) was reduced by FLZ in Abeta-expressing neuroblastoma cells, and correlated with an increase in the soluble alpha-secretase derived fragment of the amyloid-beta protein precursor (sAbetaPPalpha) in the medium. Moreover, the active form of ADAM10 and AbetaPP were elevated at the cell surface of FLZ-treated cells, consistent with an enhanced co-localization of ADAM10 and AbetaPP on the membrane. Pretreatment with brefeldin, a protein trafficking inhibitor, blocked FLZ-induced translocation of ADAM10 to the cell surface and release of sAbetaPPalpha to the culture medium. Furthermore, oral administration of FLZ to APPswe/PS1 transgenic mice significantly reduced the levels of Abeta, paralleling with activation of ADAM10, in the hippocampus. In silico prediction indicates that the structure of FLZ is compatible with the drug-like rules for absorption and permeability. These findings suggest that FLZ reduces Abeta production by promoting AbetaPP non-amyloidogenic alpha-secretase processing. As such, FLZ may have therapeutic potential for the treatment of AD.