title: Cilostazol suppresses β-amyloid production by activating a disintegrin and metalloproteinase 10 via the upregulation of SIRT1-coupled retinoic acid receptor-β.
abstract: The accumulation of plaques of β-amyloid (Aβ) peptides, a hallmark of Alzheimer's disease, results from the sequential cleavage of amyloid precursor protein (APP) by activation of β- and γ-secretases. However, the production of Aβ can be avoided by alternate cleavage of APP by α-and γ-secretases. We hypothesized that cilostazol attenuates Aβ production by increasing a disintegrin and metalloproteinase 10 (ADAM10)/α-secretase activity via SIRT1-coupled retinoic acid receptor-β (RARβ) activation in N2a cells expressing human APP Swedish mutation (N2aSwe). To evoke endogenous Aβ overproduction, the culture medium was switched from medium containing 10% fetal bovine serum (FBS) to medium containing 1% FBS, and cells were cultured for 3∼24 hr. After depletion of FBS in media, N2aSwe cells showed increased accumulations of full-length APP (FL-APP) and Aβ in a time-dependent manner (3-24 hr) in association with decreased ADAM10 protein expression. When pretreated with cilostazol (10-30 μM), FL-APP and Aβ levels were significantly reduced, and ADAM10 and α-secretase activities were restored. Furthermore, the effect of cilostazol on ADAM10 expression was antagonized by pretreating Rp-cAMPS and sirtinol and by SIRT1-gene silencing. In the N2aSwe cells overexpressing the SIRT1 gene, ADAM10, and sAPPα levels were significantly elevated. In addition, like all-trans retinoic acid, cilostazol enhanced the protein expressions of RARβ and ADAM10, and the cilostazol-stimulated ADAM10 elevation was significantly attenuated by LE135 (a RARβ inhibitor), sirtinol, and RARβ-gene silencing. In conclusion, cilostazol suppresses the accumulations of FL-APP and Aβ by activating ADAM10 via the upregulation of SIRT1-coupled RARβ.
authors.affiliation: Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Yangsan-si, Gyeongsangnam-do, Republic of Korea.
authors.forename: Hye Rin
authors.initials: HR
authors.lastname: Lee
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.forename: So Youn
authors.initials: SY
authors.lastname: Park
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Won Suk
authors.initials: WS
authors.lastname: Lee
authors.forename: Byung Yong
authors.initials: BY
authors.lastname: Rhim
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D000077407:Cilostazol; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D019483:Disintegrins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism*; D051379:Mice; D009284:Naphthols / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D001549:Benzamides; D019483:Disintegrins; D004791:Enzyme Inhibitors; D009284:Naphthols; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D013777:Tetrazoles; D013873:Thionucleotides; C078592:amyloid beta-protein (1-40); C082925:retinoic acid receptor beta; C439060:sirtinol; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP; D053829:Amyloid Precursor Protein Secretases; D053506:Matrix Metalloproteinase 10; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077407:Cilostazol
keywords: ADAM10; Alzheimer's disease; SIRT1; cilostazol