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Increased iPLA2 activity and levels of phosphorylated GSK3B in platelets are associated with donepezil treatment in Alzheimer’s disease patients

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Abstract

Reduced phospholipase A2 (PLA2) activity and increased phosphorylation of glycogen synthase kinase 3B (GSK3B) participate in the production of beta-amyloid plaques and of neurofibrillary tangles, which are two neuropathological hallmarks of Alzheimer’s disease (AD). Experimental evidences suggest a neuroprotective effect of the cholinesterase inhibitor donepezil in the treatment the disease. The aims of the present study were to evaluate in AD patients the effects of treatment with donepezil on PLA2 activity and GSK3B level. Thirty patients with AD were treated during 6 months with 10 mg daily of donepezil. Radio-enzymatic assays were used to measure PLA2 activity and Elisa assays for GSK3B level, both in platelets. Before treatment and after 3 and 6 months on donepezil, AD patients underwent a cognitive assessment and platelet samples were collected. Values were compared to a healthy control group of 42 sex- and age-matched elderly individuals. Before treatment, iPLA2 activity was lower in patients with AD as compared to controls (p < 0.001). At baseline, no differences were found in GSK3B level between both groups. After 3 and 6 months of treatment, we found a significant increase in iPLA2 activity (p = 0.015 and p < 0.001, respectively). iPLA2 increment was related to the cognitive improvement during treatment (p = 0.037). After 6 months, we found an increase in phosphorylated GSK3B (p = 0.02). The present findings suggest two possible mechanisms by which donepezil delays the progression of AD. The increment of iPLA2 activity may reduce the production of beta-amyloid plaques, whereas the phosphorylation of GSK3B inactivates the enzyme, reducing thus the phosphorylation of tau protein.

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References

  1. Leyhe T, Hoffmann N, Stransky E, Laske C (2009) Increase of SCF plasma concentration during donepezil treatment of patients with early Alzheimer’s disease. Int J Neuropsychopharmacol 12(10):1319–1326

    Article  CAS  PubMed  Google Scholar 

  2. Shen H, Kihara T, Hongo H, Wu X, Kem WR, Shimohama S, Akaike A, Niidome T, Sugimoto H (2010) Neuroprotection by donepezil against glutamate excitotoxicity involves stimulation of alpha7 nicotinic receptors and internalization of NMDA receptors. Br J Pharmacol 161(1):127–139

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Noh MY, Koh SH, Kim SM, Maurice T, Ku SK, Kim SH (2013) Neuroprotective effects of donepezil against Aβ42-induced neuronal toxicity are mediated through not only enhancing PP2A activity but also regulating GSK-3β and nAChRs activity. J Neurochem 127(4):562–574

    Article  CAS  PubMed  Google Scholar 

  4. Hashimoto M, Kazui H, Matsumoto K, Nakano Y, Yasuda M, Mori E (2005) Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer’s disease? Am J Psychiatry 162(4):676–682

    Article  PubMed  Google Scholar 

  5. Talib LL, Diniz BS, Zainaghi IA, Forlenza OV, Gattaz WF (2012) A radioenzymatic assay to identify three groups of phospholipase A(2) in platelets. Prostaglandins Leukot Essent Fatty Acids 86(4–5):149–153

    Article  CAS  PubMed  Google Scholar 

  6. Schaloske RH, Dennis EA (2006) The phospholipase A2 superfamily and its group numbering system. Biochim Biophys Acta 1761(11):1246–1259 (Review)

    Article  CAS  PubMed  Google Scholar 

  7. Burke JE, Dennis EA (2009) Phospholipase A2 structure/function, mechanism, and signaling. J Lipid Res 50(Suppl):S237–S242 (Review)

    PubMed Central  PubMed  Google Scholar 

  8. Dennis EA (1994) Diversity of group types, regulation, and function of phospholipase A2. J Biol Chem 269(18):13057–13060

    CAS  PubMed  Google Scholar 

  9. Lambeau G, Gelb MH (2008) Biochemistry and physiology of mammalian secreted phospholipases A2. Annu Rev Biochem 77:495–520

    Article  CAS  PubMed  Google Scholar 

  10. Schaeffer EL, Skaf HD, Novaes Bde A, da Silva ER, Martins BA, Joaquim HD, Gattaz WF (2011) Inhibition of phospholipase A2 in rat brain modifies different membrane fluidity parameters in opposite ways. Prog Neuropsychopharmacol Biol Psychiatry 35(7):1612–1617

    Article  CAS  PubMed  Google Scholar 

  11. Sun GY, Xu J, Jensen MD, Simonyi A (2004) Phospholipase A2 in the central nervous system: implications for neurodegenerative diseases. J Lipid Res 45(2):205–213

    Article  CAS  PubMed  Google Scholar 

  12. Schaeffer EL, Forlenza OV, Gattaz WF (2009) Phospholipase A2 activation as a therapeutic approach for cognitive enhancement in early-stage Alzheimer disease. Psychopharmacology 202(1–3):37–51

    Article  CAS  PubMed  Google Scholar 

  13. Schaeffer EL, da Silva ER, Novaes Bde A, Skaf HD, Gattaz WF (2010) Differential roles of phospholipases A2 in neuronal death and neurogenesis: implications for Alzheimer disease. Prog Neuropsychopharmacol Biol Psychiatry 34(8):1381–1389

    Article  CAS  PubMed  Google Scholar 

  14. Forlenza OV, Mendes CT, Marie SK, Gattaz WF (2007) Inhibition of phospholipase A2 reduces neurite outgrowth and neuronal viability. Prostaglandins Leukot Essent Fatty Acids 76:47–55

    Article  CAS  PubMed  Google Scholar 

  15. De-Paula VJ, Schaeffer EL, Talib LL, Gattaz WF, Forlenza OV (2010) Inhibition of phospholipase A2 increases tau phosphorylation at Ser214 in embryonic rat hippocampal neurons. Prostaglandins Leukot Essent Fatty Acids 82:57–60

    Article  CAS  PubMed  Google Scholar 

  16. Schaeffer EL, Gattaz WF (2005) Inhibition of calcium-independent phospholipase A2 activity in rat hippocampus impairs acquisition of short- and long-term memory. Psychopharmacology 181:392–400

    Article  CAS  PubMed  Google Scholar 

  17. Schaeffer EL, Gattaz WF (2007) Requirement of hippocampal phospholipase A2 activity for long-term memory retrieval in rats. J Neural Transm 114:379–385

    Article  CAS  PubMed  Google Scholar 

  18. Schaeffer EL, Zorron PuL, Gagliotti DA, Gattaz WF (2009) Conditioning training and retrieval increase phospholipase A(2) activity in the cerebral cortex of rats. J Neural Transm 116:41–50

    Article  CAS  PubMed  Google Scholar 

  19. Gattaz WF, Maras A, Cairns NJ, Levy R, Förstl H (1995) Decreased phospholipase A2 activity in Alzheimer brains. Biol Psychiatry 37:13–17

    Article  CAS  PubMed  Google Scholar 

  20. Gattaz WF, Cairns NJ, Levy R, Förstl H, Braus DF, Maras A (1996) Decreased phospholipase A2 activity in the brain and in platelets of patients with Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 246(3):129–131

    Article  CAS  PubMed  Google Scholar 

  21. Talbot K, Young RA, Jolly-Tornetta C, Lee VM, Trojanowski JQ, Wolf BA (2000) A frontal variant of Alzheimer’s disease exhibits decreased calcium-independent phospholipase A2 activity in the prefrontal cortex. Neurochem Int 37(1):17–31

    Article  CAS  PubMed  Google Scholar 

  22. Forlenza OV, Wacker P, Nunes PV, Yacubian J, Castro CC, Otaduy MC, Gattaz WF (2005) Reduced phospholipid breakdown in Alzheimer’s brains: a 31P spectroscopy study. Psychopharmacology 180(2):359–365

    Article  CAS  PubMed  Google Scholar 

  23. Embi N, Rylatt DB, Cohen P (1980) Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem 107:519–527

    Article  CAS  PubMed  Google Scholar 

  24. Chin PC, Majdzadeh N, D’Mello SR (2005) Inhibition of GSK3b is a common event in neuroprotection by different survival factors. Mol Brain Res 137:193–201

    Article  CAS  PubMed  Google Scholar 

  25. Balaraman Y, Limaye ER, Levey AI, Srinivasan S (2006) Glycogen synthase kinase 3B and Alzheimer’s disease: pathophysiological and therapeutic significance. Cell Mol Life Sci 63:1226–1235

    Article  CAS  PubMed  Google Scholar 

  26. Jope RS, Yuskaitis CJ, Beurel E (2007) Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res 32:577–595

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Peineau S, Bradley C, Taghibiglou C, Doherty A, Bortolotto ZA, Wang YT et al (2008) The role of gsk-3 in synaptic plasticity. Br J Pharmacol 153(Suppl. 1):S428–S437

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Muyllaert D, Kremer A, Jaworski T, Borghgraef P, Devijver H, Croes S et al (2008) Glycogen synthase kinase-3b, or a link between amyloid and tau pathology? Genes. Brain Behav 7:57–66

    CAS  Google Scholar 

  29. Grimes CA, Jope RS (2001) The multifaceted roles of GSK3b in cellular signaling. Prog Neurobiol 65:391–426

    Article  CAS  PubMed  Google Scholar 

  30. Gould TD, Manji HK (2005) Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs. Neuropsychopharmacology 30:1223–1237

    CAS  PubMed  Google Scholar 

  31. Wang QM, Fiol CJ, DePaoli-Roach AA, Roach PJ (1994) Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation. J Biol Chem 269:14566–14574

    CAS  PubMed  Google Scholar 

  32. Ly PT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, Zhang M, Yang Y, Cai F, Woodgett J, Song W (2013) Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Invest 123(1):224–235

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34(7):939–944

    Article  CAS  PubMed  Google Scholar 

  34. Roth M, Tym E, Mountjoy CQ, Huppert FA, Hendrie H, Verma S, Goddard R (1986) CAMDEX: a standardized Instrument for the diagnosis of mental disorders in the elderly with special reference to early detection of dementia. Br J Psychiatry 149:698–709

    Article  CAS  PubMed  Google Scholar 

  35. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198

    Article  CAS  PubMed  Google Scholar 

  36. Talib LL, Yassuda MS, Diniz BS, Forlenza OV, Gattaz WF (2008) Cognitive training increases platelet PLA2 activity in healthy elderly subjects. Prostaglandins Leukot Essent Fatty Acids 78:265–269

    Article  CAS  PubMed  Google Scholar 

  37. Forlenza OV, Torres CA, Talib LL, de Paula VJ, Joaquim HP, Diniz BS (2011) Increased platelet GSK3B activity in patients with mild cognitive impairment and Alzheimer’s disease. J Psychiatr Res 45(2):220–224

    Article  PubMed  Google Scholar 

  38. Diniz BS, Talib LL, Joaquim HPG, De-Paula VRJ, Gattaz WF, Forlenza OV (2011) Platelet GSK3B activity in patients with late-life depression: marker of depressive episode severity and cognitive impairment? World J Biol Psychiatry 12(3):216–222

    Article  PubMed  Google Scholar 

  39. Joaquim HP, Talib LL, Forlenza OV, Diniz BS, Gattaz WF (2012) Long-term sertraline treatment increases expression and decreases phosphorylation of glycogen synthase kinase-3B in platelets of patients with late-life major depression. J Psychiatr Res 46(8):1053–1058

    Article  PubMed  Google Scholar 

  40. Selkoe DJ (2004) American College of Physicians; American Physiological Society. Alzheimer disease: mechanistic understanding predicts novel therapies. Ann Intern Med 140(8):627–638 (Review)

    Article  CAS  PubMed  Google Scholar 

  41. Noh MY, Koh SH, Kim Y, Kim HY, Cho GW, Kim SH (2009) Neuroprotective effects of donepezil through inhibition of GSK-3 activity in amyloid-beta-induced neuronal cell death. J Neurochem 108(5):1116–1125

    Article  CAS  PubMed  Google Scholar 

  42. Gattaz WF, Talib LL, Schaeffer EL, Diniz BS, Forlenza OV (2014) Low platelet iPLA2 activity predicts conversion from mild cognitive impairment to Alzheimer’s disease: a 4-year follow-up study. J Neural Transm 121(2):193–200

    Article  CAS  PubMed  Google Scholar 

  43. Smesny S, Stein S, Willhardt I, Lasch J, Sauer H (2008) Decreased phospholipase A2 activity in cerebrospinal fluid of patients with dementia. J Neural Transm 115(8):1173–1179

    Article  CAS  PubMed  Google Scholar 

  44. Akasofu S, Kimura M, Kosasa T, Ogura H, Sawada K (2006) Protective effect of donepezil in primary-cultured rat cortical neurons exposed to N-methyl-d-aspartate (NMDA) toxicity. Eur J Pharmacol 530(3):215–222

    Article  CAS  PubMed  Google Scholar 

  45. Zhang D, Shooshtarizadeh P, Laventie BJ, Colin DA, Chich JF, Vidic J, de BarryJ Chasserot-Golaz S, Delalande F, Van Dorsselaer A, Schneider F, Helle K, Aunis D, Prévost G, Metz-Boutigue MH (2009) Two chromogranin a-derived peptides induce calcium entry in human neutrophils by calmodulin-regulated calcium independent phospholipase A2. PLoS ONE 4(2):e4501

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The present work was supported by FAPESP, Fundação de Amparo à Pesquisa do Estado de São Paulo (Grants Nos. 02/13633-7 and 09/52825-8). The Laboratory of Neuroscience receives financial support from Associação Beneficente Alzira Denise Hertzog da Silva (ABADHS) and from the JNK Empreendimentos e Incorporações.

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Authors and Affiliations

  1. Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil

    L. L. Talib, S. R. Hototian, H. P. G. Joaquim, O. V. Forlenza & W. F. Gattaz

  2. Instituto de Psiquiatria, Hospital das Clínicas da Faculdade de Medicina da USP, Rua Dr. Ovídio Pires de Campos 785, São Paulo, SP, 05403-010, Brazil

    W. F. Gattaz

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  1. L. L. Talib
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Correspondence to L. L. Talib.

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Talib, L.L., Hototian, S.R., Joaquim, H.P.G. et al. Increased iPLA2 activity and levels of phosphorylated GSK3B in platelets are associated with donepezil treatment in Alzheimer’s disease patients. Eur Arch Psychiatry Clin Neurosci 265, 701–706 (2015). https://doi.org/10.1007/s00406-015-0600-6

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  • DOI: https://doi.org/10.1007/s00406-015-0600-6

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