A Natural Squamosamide Derivative FLZ Reduces Amyloid-β Production by Increasing Non-Amyloidogenic AβPP Processing

Substantial evidence supports a central role of A beta 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 (A beta) was reduced by FLZ in A beta-expressing neuroblastoma cells, and correlated with an increase in the soluble alpha-secretase derived fragment of the amyloid-beta protein precursor (sA beta PP alpha) in the medium. Moreover, the active form of ADAM10 and A beta PP were elevated at the cell surface of FLZ-treated cells, consistent with an enhanced co-localization of ADAM10 and A beta PP on the membrane. Pretreatment with brefeldin, a protein trafficking inhibitor, blocked FLZ-induced translocation of ADAM10 to the cell surface and release of sA beta PP alpha to the culture medium. Furthermore, oral administration of FLZ to APPswe/PS1 transgenic mice significantly reduced the levels of A beta, 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 A beta production by promoting A beta PP non-amyloidogenic alpha-secretase processing. As such, FLZ may have therapeutic potential for the treatment of AD.