Z-10 And Its Derivatives Target RXRα To Remove Aβ In The Brain Of AD Mice

RXRa is an important member of nuclear receptor superfamily,and belongs to non-steroid hormone receptor family.It is a ligand-regulated transcriptionalfactor that participates in almost all of the physiological activities in the human body,including metabolism,growth,development,differentiation,and immunity.Its dysfunction is closely related to many human diseases.Cramer and his colleagues reported that RXRa agonist Bexarotene,which was approved by the US Food and Drug Administration for the treatment of certain types of skin T-cell lymphoma,can enhance the expression of ABCA1,ApoE and other lipid metabolism-related proteins by transactivation of LXR/RXR and PPAR/RXR,resulting inamyloid β(Aβ)-protein clearance and reduction of Aβ plaques in the brain of APP mice,and improvement of mouse cognitive deficits.We have previously reported that Z-10 is a unique ligand of RXRa.Different from the traditional RXRa ligands with a carboxyl group,Z-10 has a nitrostyrenegroup instead.We hypothesized that Z-10 like Bexarotenemight have the beneficial effect to AD.We designed and synthesized a series of Z-10 derivatives by adding methyl,hydroxyl,and methoxy groups at the para or ortho sites of nitrostyrene group.Our reporter gene assays showed that derivatives with methyl and methoxy groups at the ortho site had more potent effects on transactivation of Gal4-DBD-RXRα-LBD and RXRα homodimers as well as RXRα heterodimers.This suggested that the ortho site was better than the para site for modification in terms of RXRα transactivation.The derivatives with hydroxyl at both the para and ortho sites failed to tansactivate RXRα,indicating the modification with strong polar group may damage Z-10 transactivating RXRα.In consistent,the derivatives with more potent ability of RXRα transactivation had higher RXRα binding affinity.We then synthesized four more Z-10 ortho derivatives.Among them we found that Z-36 with ortho ethoxy modification had more potent and stronger transactivation of RXRα.We then explored the effect of Z-10 and Z-36 on APP mice model(an AD mice model).Both Z-10 and Z-36 enhanced the expression of ABCA1 and ApoE in BV2 cells,a murine microglial cell line,of which Z-36 had stronger effect.More importantly,Z-10 and Z-36 significantly remove Aβ plaques and increased ABCA1 expression in the hippocampus of APP mice,both of which Z-36 had stronger effect.These results indicated that Z-10 and Z-36 transactivated LXR/RXR and PPAR/RXR to upregulate the expressions of ApoE and ABCA1,leading to the clearance of Aβ.The stronger anti-AD effect of Z-36 resulted from its stronger effect on RXRαtransactivation.This research elucidates the structure-activity relationship of Z-10 derivatives to a certain degree.We found that ortho is the better site for modification to transactivateRXRα,which lay the basis for further optimizing Z-10.The results from this research also reveal the beneficial effect of Z-10 on AD and the underlying mechanism,as well as an optimized derivative Z-36.Future investigation based on this may provide a lead compound for AD treatment.