title: Attenuation of β-amyloid-induced tauopathy via activation of CK2α/SIRT1: targeting for cilostazol.
abstract: β-Amyloid (Aβ) deposits and hyperphosphorylated tau aggregates are the chief hallmarks in the Alzheimer's disease (AD) brains, but the strategies for controlling these pathological events remain elusive. We hypothesized that CK2-coupled SIRT1 activation stimulated by cilostazol suppresses tau acetylation (Ac-tau) and tau phosphorylation (P-tau) by inhibiting activation of P300 and GSK3β. Aβ was endogenously overproduced in N2a cells expressing human APP Swedish mutation (N2aSwe) by exposure to medium containing 1% fetal bovine serum for 24 hr. Increased Aβ accumulation was accompanied by increased Ac-tau and P-tau levels. Concomitantly, these cells showed increased P300 and GSK3β P-Tyr216 expression; their expressions were significantly reduced by treatment with cilostazol (3-30 μM) and resveratrol (20 μM). Moreover, decreased expression of SIRT1 and its activity by Aβ were significantly reversed by cilostazol as by resveratrol. In addition, cilostazol strongly stimulated CK2α phosphorylation and its activity, and then stimulated SIRT1 phosphorylation. These effects were confirmed by using the pharmacological inhibitors KT5720 (1 μM, PKA inhibitor), TBCA (20 μM, inhibitor of CK2), and sirtinol (20 μM, SIRT1 inhibitor) as well as by SIRT1 gene silencing and overexpression techniques. In conclusion, increased cAMP-dependent protein kinase-linked CK2/SIRT1 expression by cilostazol can be a therapeutic strategy to suppress the tau-related neurodegeneration in the AD brain.
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: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D000077407:Cilostazol; D005455:Fluorescent Antibody Technique; D006801:Humans; D053557:Keratin-2 / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000096:biosynthesis*; D024801:Tauopathies / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053557:Keratin-2; D018696:Neuroprotective Agents; D013777:Tetrazoles; D016875:tau Proteins; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077407:Cilostazol
keywords: CK2α; SIRT1; cilostazol; tau, GSK-3β; β-amyloid