title: Decrease of Amyloid-β Levels by Curcumin Derivative via Modulation of Amyloid-β Protein Precursor Trafficking.
abstract: The abnormal production and deposition of amyloid-β (Aβ) peptides is a pathologic hallmark of Alzheimer's disease. Aβ is generated from amyloid-β protein precursor (AβPP) by two sequential proteolytic cleavage steps involving β- and γ-secretases in the trans-Golgi network and endosomes. Since direct inhibition of secretase could induce undesirable side-effects due to inadvertent inhibition of unrelated secretase substrates, it is important to establish methods for inhibiting Aβ production that do not affect secretase activity. It has been suggested that curcumin may have potent anti-amyloidogenic effect. In the present study, we evaluate the effect of curcumin derivatives on Aβ production in human neuroblastoma SH-SY5Y cells and in CHO cells which stably express human AβPP (CHO-AβPP). We found that the curcumin derivative CU6 was more effective than curcumin itself in reducing Aβ secretion. We further found that in SH-SY5Y cells CU6 inhibited neither β- nor γ-secretase activity, and that increased amounts of immature forms of AβPP accumulated in the endoplasmic reticulum (ER). We also found that CU6 induced expression of the ER chaperone glucose-regulated protein 78 (GRP78), and enhanced formation of the AβPP/GRP78 complex. These results suggest that CU6 downregulates intracellular AβPP trafficking, resulting in suppression of Aβ production independently of secretase activity.
authors.affiliation: Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Kotani
authors.affiliation: Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
authors.forename: Yasuomi
authors.initials: Y
authors.lastname: Urano
authors.affiliation: Graduate School of Brain Science, Doshisha University, Kyoto, Japan.
authors.forename: Hachiro
authors.initials: H
authors.lastname: Sugimoto
authors.affiliation: Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Noguchi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003412:Cricetulus; D003474:Curcumin / Q000031:analogs & derivatives*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D003474:Curcumin
keywords: Alzheimer’s disease; amyloid-β peptides; curcumin derivatives; endoplasmic reticulum