title: Polyhydroxycurcuminoids but not curcumin upregulate neprilysin and can be applied to the prevention of Alzheimer's disease.
abstract: Neprilysin (NEP) is the most important Aβ-degrading enzyme. Its expression level decreases with age and inversely correlated with amyloid accumulation, suggesting its correlation with the late-onset of Alzheimer's disease. Recently, many reports showed that upregulating NEP level is a promising strategy in the prevention and therapy of Alzheimer's disease. Here, we used a sensitive fluorescence-based Aβ digestion assay to screen 25 curcumin analogs for their ability to upregulate NEP activity. To our surprise, four compounds, dihydroxylated curcumin, monohydroxylated demethoxycurcumin, and mono- and di-hydroxylated bisdemethoxycurcumin, increased NEP activity, while curcumin did not. The ability of these polyhydroxycurcuminoids to upregulate NEP was further confirmed by mRNA and protein expression levels in the cell and mouse models. Finally, feeding monohydroxylated demethoxycurcumin (also named demethylcurcumin) or dihydroxylated bisdemethoxycurcumin (also named bisdemethylcurcumin) to APPswe/PS1dE9 double transgenic mice upregulated NEP levels in the brain and reduced Aβ accumulation in the hippocampus and cortex. These polyhydroxycurcuminoids offer hope in the prevention of Alzheimer's disease.
authors.affiliation: Institute of Biochemical Sciences, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei 106, Taiwan.|Institute of Biological Chemistry, Academia Sinica, No. 128, Sec. 2, Academia Rd., Nankang, Taipei 115, Taiwan.
authors.forename: Po-Ting
authors.initials: PT
authors.lastname: Chen
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, No. 128, Sec. 2, Academia Rd., Nankang, Taipei 115, Taiwan.
authors.forename: Zih-Ten
authors.initials: ZT
authors.lastname: Chen
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University, No. 250, Wuxing St., Taipei 110, Taiwan.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Hou
authors.affiliation: Institute of Biochemical Sciences, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei 106, Taiwan.
authors.forename: Lung-Chih
authors.initials: LC
authors.lastname: Yu
authors.affiliation: Institute of Biochemical Sciences, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei 106, Taiwan.|Institute of Biological Chemistry, Academia Sinica, No. 128, Sec. 2, Academia Rd., Nankang, Taipei 115, Taiwan.
authors.forename: Rita P-Y
authors.initials: RP
authors.lastname: Chen
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D015260:Neprilysin; D003474:Curcumin