Abstract
Statins are a class of cholesterol-lowering drugs and have been suggested therapeutic use for neurodegenerative diseases including Alzheimer's disease (AD). Our recent studies revealed a neuronal protective effect of lovastatin (LOV) from N-methyl-d-aspartic acid (NMDA) excitotoxicity. The neuroprotective mechanism of statins, however, is far unknown. Here we demonstrated that LOV suppressed the aberrant tau phosphorylation both from frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) mutation and okadaic acid (OA) induction in cultured rat primary neurons. The protective effect of LOV occurred at multiple pathological sites of tau protein, including Tyr181, Tyr231 Ser202/Tyr205, Tyr212/Ser214 and Ser396/Ser404. Further analysis revealed that the potential mechanism of the suppressive effect of LOV resulted from two aspects, activating OA-inhibited protein phosphatase 2A (PP2A) activity and attenuating OA-induced activity of tau kinases CDK5/P25 and CDK2/4, but not glycogen synthase kinase 3β (GSK3β). These findings give new insights into the molecular mechanism of LOV-mediated neuroprotective effect and provide experimental evidence for its therapeutic use in AD.
References
Sep 1, 1993·Journal of Neurochemistry·C X GongK Iqbal
Sep 1, 1995·Molecular Biology of the Cell·R Y PoonT Hunter
Jan 1, 1997·Journal of Neuropathology and Experimental Neurology·J J PeiI Grundke-Iqbal
Nov 12, 1998·Oncogene·S RaoK Keyomarsi
May 14, 1999·Genes & Development·A MontagnoliM Pagano
Jul 8, 1999·Proceedings of the National Academy of Sciences of the United States of America·S RaoK Keyomarsi
Dec 5, 2000·Molecular Biology of the Cell·V Vogelsberg-RagagliaV M Lee
Feb 24, 2001·Journal of Neurochemistry·Q W FanM Michikawa
Aug 28, 2002·Biochemical Society Transactions·B Wolozin
Nov 3, 2005·The European Journal of Neuroscience·Fei LiuCheng-Xin Gong
Apr 28, 2006·Neuroreport·SeungYong YoonDongHou Kim
Jul 27, 2006·Acta Neurologica Scandinavica. Supplementum·B WolozinA McKee
Jul 25, 2007·The Journal of Biological Chemistry·Stephen M OstrowskiGary Landreth
Feb 20, 2009·Journal of Neuropathology and Experimental Neurology·Moran BoimelHanna Rosenmann
May 12, 2009·Progress in Neurobiology·Peter J van der MostUlrich L M Eisel
Apr 22, 2010·Experimental Neurology·Qing WangMidori A Yenari
May 12, 2010·Brain Research·Zhang Zhang, James W Simpkins
Jan 22, 2011·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Avik Roy, Kalipada Pahan
Sep 3, 2011·Journal of Neurochemistry·Rolf Postina
Citations
Jun 14, 2015·Cellular and Molecular Life Sciences : CMLS·Dave J KossGernot Riedel
May 18, 2016·Experimental Biology and Medicine·Liang ZhaoZhi-Zhong Guan
Nov 10, 2017·FEBS Letters·Goce Taleski, Estelle Sontag
Dec 27, 2016·Evidence-based Complementary and Alternative Medicine : ECAM·Yu CaoHao Li
Feb 27, 2020·International Journal of Molecular Sciences·Yu-Chia KaoKuen-Jer Tsai
Jul 25, 2021·Behavioural Brain Research·RuoLan CaiZhiyou Cai