Prevention of isoproterenol-induced tau hyperphosphorylation by melatonin in the rat

( views:93, downloads:0 )
WANG Xiao-chuan()
ZHANG Jing()
YU Xian()
HAN Liu()
ZHOU Zhen-tao()
WANG Jian-zhi()
Journal Title:
Volume 57, Issue 01, 2005
Key Word:
Alzheimer's disease;melatonin;isoproterenol;tau;hyperphosphorylation

Abstract: Hyperphosphorylated microtubule-associated protein tau is the major protein component of neurofibrillary tangles in the brain of patients with Alzheimer's disease (AD). Until now, there is no effective cure to arrest this hyperphosphorylation. The present study was designed to explore the in vivo preventive effect of melatonin on Alzheimer-like tau hyperphosphorylation. Isoproterenol,a β-receptor agonist, was used to induce tau hyperphosphorylation, and for preventive effect of melatonin, the rats were injected intraperitoneally with melatonin for 5 d before hippocampi infusion of isoproterenol. The level of tau phosphorylation was detected by Western blot and immunohistochemistry using sites specific antibodies (PHF-1 and Tau-l), and it was normalized by nonphosphorylation dependent total tau antibody (11 le). The results by Western blot showed that the immunoreaction of tau at PHF-1 epitope was enhanced, and the reaction at Tau-1 epitope was weakened significantly at 48 h after injection of isoproterenol, suggesting hyperphosphorylation of tau at Ser 396/Ser 404 (PHF-1) and Ser199/Ser 202 (Tau-1) sites. Similar results were observed by immunohistochemistry staining, in which hyperphosphorylated tau was mainly detected in mossy fibers of hippocampal CA3 region. Preinjection of rats with melatonin intraperitoneally arrested effectively the isoproterenol-induced tau hyperphosphorylation at both Tau1 and PHF-1 sites, implying the preventive effect of melatonin in Alzheimer-like tau hyperphosphorylation.

  • [1]SelkoeDJ. Alzheimer'sdiseaseisasynapticfailure. Science2002;298(5594): 789-791.
  • [2]Feany MB, Dickson DW. Neurodegenerative disorders with extensive tau pathology: a comparative study and review. Ann Neurol 1996; 40(2): 139-148.
  • [3]Iqbal K, Grundke-Iqbal I, Smith AJ, George L, Tung YC, Zaidi T.Identification and localization of a tau peptide to paired helical filaments of Alzheimer disease. Proc Natl Acad Sci USA 1989;86(14): 5646-5650.
  • [4]Wang JZ, Gong CX, Zaidi T, Grundke-Iqbal I, Iqbal K. Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J Biol Chem 1995; 270(9): 4854-4860.
  • [5]Avila J, Lucas JJ, Perez M, Hernandez F. Role of tau protein in both physiological and pathological conditions. Physiol Rev 2004; 84(2): 361-384.
  • [6]Wang XC, Hu ZH, Fang ZY, Feng Y, Yang YH, Wang Q, Tang XW, Wu YG, Wang JZ. Correlation of Alzheimer-like tau abnormal hyperphosphorylation and fMRI BOLD signal intensity.Current Alzheimer Res 2004; 1(2): 143-145.
  • [7]LingZQ, Wang XC, ZhangSH, ZhangYP, WangJZ. Protection of melatonin on isoproterenol-induced hyperphosphorylation of tau and spatial memory impairment in rats. Chin J Pathophys (中国病理生理学杂志) 2004; 20(1): 6-11.
  • [8]Magri F, Sarra S, Cinchetti W, Guazzoni V, Fioravanti M, Cravello L, Ferrari E. Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians.J Pineal Res 2004; 36(4): 256-261.
  • [9]Lahiri DK, Ge YW, Sharman EH, BondySC. Age-relatedchanges in serum melatonin in mice: higher levels of combined melatonin and 6-hydroxymelatonin sulfate in the cerebral cortex than serum,heart, liver and kidney tissues. J Pineal Res 2004; 36(4): 217-223.
  • [10]Liu RY, Zhou JN, van Heerikhuize J, Hofman MA, Swaab DF.Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein Eepsilon4/4 genotype. J Clin Endocrinol Metab 1999; 84(1):323-327.
  • [11]Wu YH, Feenstra MG, Zhou JN, Liu RY, Torano JS, Van Kan HJ, Fischer DF, Ravid R, Swaab DF. Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. J Clin Endocrinol Metab 2003; 88(12): 5898-5906.
  • [12]Liu SJ and Wang JZ. Alzheimer-like tau phosphorylationinduced by wortmannin in vivo and its attenuation by melation. Acta Pharmacol Sin 2002; 23(2): 183-187.
  • [13]Li SP, Deng YQ, Wang XC, Wang YP, Wang JZ. Melatonin protects S H- S Y 5 Y neuroblastoma cells from calyculin A-induced neurofilament impairment and neurotoxicity. J Pineal Res 2004;36(3): 186-191.
  • [14]Paxinos G, Watson C, Pennisi M, Topple A. Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods 1985; 13(2):139-143.
  • [15]Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227(259): 680-685.
  • [16]Wang JZ, Wu Q, Smith A, Grundke-Iqbal I, Iqbal K. Tau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase. FEBS Lett 1998; 436(1):28-34.
  • [17]Singh TJ, Zaidi T, Grundke-Iqbal I, Iqbal K. Non-proline-dependent protein kinases phosphorylate several sites found in tau from Alzheimer disease brain. Mol Cell Biochem 1996; 154 (2): 143-151.
  • [18]Litersky JM, Johnson GV, Jakes R, Goedert M, Lee M, Seubert P. Tau protein is phosphorylated by cyclic AMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase Ⅱ within its microtubule-binding domains at Ser-262 and Ser356. Biochem J 1996; 316(Pt 2): 655-660.
  • [19]Reynolds CH, Utton MA, Gibb GM, Yates A, Anderton BH.Stress-activated protein kinase/c-jun N-terminal kinase phosphorylates tau protein. J Neurochem 1997; 68(4): 1736-1744.
  • [20]Wang JZ, Wang XC, Liu R, Wang Q, Grundke-Iqbal I, Iqbal K. In vitro analysis of tau phosphorylation sites and its biological activity. Chin Med Sci J 2002; 17(1): 13-16.
  • [21]Korf HW, Von Gall C, Stehle J. The circadian system and melatonin: lessons from rats and mice. Chronobiol Int 2003; 20 (4): 697-710.
  • [22]Skwarlo-Sonta K. Melatonin in immunity: comparative aspects.Neuroendocrinol Lett 2002; 23 (Suppl 1): 61-66.
  • [23]Tan DX, Reiter R J, Manchester LC, Yan MT, El-Sawi M, Sainz RM, Mayo JC, Kohen R, Allegra M, Hardeland R. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2002; 2(2): 181-197.
  • [24]Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, Reiter RJ. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 2004; 36(1): 1-9.
  • [25]Weinstock M, Shoham S. Rat models of dementia based on reductions in regional glucose metabolism, cerebral blood flow and cytochrome oxidase activity. J Neural Transm 2004; 111 (3):347-366.
  • [26]Zhang YC, Wang ZF, Wang Q, Wang YP, Wang JZ. Melatonin attenuates beta-amyloid-induced inhibition of neurofilament expression. Acta Pharmacol Sin 2004; 25(4): 447-451.
  • [27]Shen YX, Xu SY, Wei W, Sun XX, Liu LH, Yang J, Dong C. The protective effects of melatonin from oxidative damage induced by amyloid beta-peptide 25-35 in middle-aged rats. J Pineal Res 2002; 32(2): 85-89.
  • [28]Pappolla MA, Simovich MJ, Bryant-Thomas T, Chyan Y J,Poeggeler B, Dubocovich M, Bick R, Perry G, Cruz-Sanchez F,Smith MA. The neuroprotective activities of melatonin against the Alzheimer beta-protein are not mediated by melatonin membrane receptors. J Pineal Res 2002; 32(3): 135-142.
WanfangData CO.,Ltd All Rights Reserved
About WanfangData | Contact US
Healthcare Department, Fuxing Road NO.15, Haidian District Beijing, 100038 P.R.China
Tel:+86-010-58882616 Fax:+86-010-58882615