A Natural Squamosamide Derivative FLZ Reduces Amyloid-beta Production by Increasing Non-Amyloidogenic AbetaPP Processing.

J Alzheimers Dis. 2009 Jul 20; Hou Y, Yu YB, Liu G, Luo YSubstantial 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 production of amyloid-beta (Abeta) was reduced by FLZ in Abeta-expressing neuroblastoma cells, which correlates 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, parallel with activation of ADAM10, in the hippocampus. In silico prediction indicates that the structure of FLZ agree with the drug-like rules for absorption and permeability. These findings suggest that reducing Abeta production by FLZ may be mediated by its promotion of AbetaPP non-amyloidogenic alpha-secretase processing, and FLZ has therapeutic potential for the treatment of AD.