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Clozapine Improves Memory Impairment and Reduces Aβ Level in the Tg-APPswe/PS1dE9 Mouse Model of Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is a progressive degenerative condition. In order to treat AD, the use of a “drug repositioning” or “repurposing” approach with potential disease-modifying compounds has been increased. The new generation antipsychotics are commonly used in AD and other dementias for the treatment of psychosis and behavioral symptoms, and several animal models have shown the effects of these potential disease-modifying compounds. In this study, we examined whether long-term clozapine treatment could reduce amyloid beta (Aβ) deposition and cognitive impairment in transgenic mice of AD, Tg-APPswe/PS1dE9. AD mice were fed clozapine at 20 mg/kg/day for 3 months from 4.5 months of age. Intake of clozapine improved the Aβ-induced memory impairment and suppressed Aβ levels and plaque deposition in the brain of AD mice. Clozapine upregulated Trk, brain-derived neurotrophic factor, cyclin-dependent kinase-5, and p35 in the cortex and hippocampus of AD mice and activated AMP-activated protein kinase (AMPK). As a downstream effector of AMPK, beta-secretase expression was decreased by clozapine administration. Moreover, clozapine-phosphorylated synapsin I at Ser9 and Ser549 sites in the hippocampus and cortex of AD mice, which may be involved in synaptic strength. This study suggests that as one of candidate for multi-target approach of AD treatment, clozapine is proposed as a therapeutic drug for treatment of AD patients.

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References

  1. Alzheimer’s Association (2012) 2012 Alzheimer’s disease facts and figures. Alzheimers Dement 8(2):131–168

    Article  Google Scholar 

  2. Araki W (2013) Potential repurposing of oncology drugs for the treatment of Alzheimer’s disease. BMC Med 11:82

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hayes CD, Dey D, Palavicini JP, Wang H, Patkar KA, Minond D, Nefzi A, Lakshmana MK (2013) Striking reduction of amyloid plaque burden in an Alzheimer’s mouse model after chronic administration of carmustine. BMC Med 11:81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Appleby BS, Nacopoulos D, Milano N, Zhong K, Cummings JL (2013) A review: treatment of Alzheimer’s disease discovered in repurposed agents. Dement Geriatr Cogn Disord 35(1–2):1–22

    Article  CAS  PubMed  Google Scholar 

  5. Honig LS, Boyd CD (2013) Treatment of Alzheimer’s disease: current management and experimental therapeutics. Curr Transl Geriatr Exp Gerontol Rep 2(3):174–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nemeroff CB, Kinkead B, Goldstein J (2002) Quetiapine: preclinical studies, pharmacokinetics, drug interactions, and dosing. J Clin Psychiatry 63(Suppl 13):5–11

    CAS  PubMed  Google Scholar 

  7. Zhu S, Shi R, Li V, Wang J, Zhang R, Tempier A, He J, Kong J, Wang JF, Li XM (2014) Quetiapine attenuates glial activation and proinflammatory cytokines in APP/PS1 transgenic mice via inhibition of nuclear factor-κB pathway. Int J Neuropsychopharmacol 18(3). doi: 10.1093/ijnp/pyu022

  8. Roth BL, Sheffler DJ, Kroeze WK (2004) Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 3(4):353–359

    Article  CAS  PubMed  Google Scholar 

  9. Buccafusco JJ (2009) Multifunctional receptor-directed drugs for disorders of the central nervous system. Neurotherapeutics 6(1):4–13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. León R, Garcia AG, Marco-Contelles J (2013) Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer’s disease. Med Res Rev 33(1):139–189

    Article  PubMed  Google Scholar 

  11. Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR (2001) Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 7(6):157–165

    Article  Google Scholar 

  12. Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22(3):659–661

    Article  CAS  PubMed  Google Scholar 

  13. Terry AV Jr, Hill WD, Parikh V, Waller JL, Evans DR, Mahadik SP (2003) Differential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats. Neuropsychopharmacology 28(2):300–309

    Article  CAS  PubMed  Google Scholar 

  14. Barak Y, Wittenberg N, Naor S, Kutzuk D, Weizman A (1999) Clozapine in elderly psychiatric patients: tolerability, safety, and efficacy. Compr Psychiatry 40(4):320–325

    Article  CAS  PubMed  Google Scholar 

  15. Oberholzer AF, Hendriksen C, Monsch AU, Heierli B, Stähelin HB (1992) Safety and effectiveness of low-dose clozapine in psychogeriatric patients: a preliminary study. Int Psychogeriatr 4(2):187–195

    Article  CAS  PubMed  Google Scholar 

  16. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11(1):47–60

    Article  CAS  PubMed  Google Scholar 

  17. Seyb KI, Ansar S, Li G, Bean J, Michaelis ML, Dobrowsky RT (2007) p35/Cyclin-dependent kinase 5 is required for protection against beta-amyloid-induced cell death but not tau phosphorylation by ceramide. J Mol Neurosci 31(1):23–35

    Article  CAS  PubMed  Google Scholar 

  18. Jeon S, Kim Y, Chung IW, Kim YS (2015) Clozapine induces chloride channel-4 expression through PKA activation and modulates CDK5 expression in SH-SY5Y and U87 cells. Prog Neuropsychopharmacol Biol Psychiatry 56:168–173

    Article  CAS  PubMed  Google Scholar 

  19. Murer MG, Yan Q, Raisman-Vozari R (2001) Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 63(1):71–124

    Article  CAS  PubMed  Google Scholar 

  20. Siegel GJ, Chauhan NB (2000) Neurotrophic factors in Alzheimer’s and Parkinson’s disease brain. Brain Res Brain Res Rev 33(2–3):199–227

    Article  CAS  PubMed  Google Scholar 

  21. Counts SE, Nadeem M, Wuu J, Ginsberg SD, Saragovi HU, Mufson EJ (2004) Reduction of cortical TrkA but not p75(NTR) protein in early-stage Alzheimer’s disease. Ann Neurol 56(4):520–531

    Article  CAS  PubMed  Google Scholar 

  22. Lally J, Gallagher A, Bainbridge E, Avalos G, Ahmed M, McDonald C (2013) Increases in triglyceride levels are associated with clinical response to clozapine treatment. J Psychopharmacol 27(4):401–403

    Article  CAS  PubMed  Google Scholar 

  23. Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther 138(2):155–175

    Article  CAS  PubMed  Google Scholar 

  24. Cai Z, Yan LJ, Li K, Quazi SH, Zhao B (2012) Roles of AMP-activated protein kinase in Alzheimer’s disease. Neuromolecular Med 14(1):1–14

    Article  CAS  PubMed  Google Scholar 

  25. Autry AE, Monteggia LM (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64(2):238–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pedrós I, Petrov D, Allgaier M, Sureda F, Barroso E, Beas-Zarate C, Auladell C, Pallàs M, Vázquez-Carrera M, Casadesús G, Folch J, Camins A (2014) Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer’s disease. Biochim Biophys Acta 1842(9):1556–1566

    Article  PubMed  Google Scholar 

  27. Kim MK, Kim SH, Yu HS, Park HG, Kang UG, Ahn YM, Kim YS (2012) The effect of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex. Int J Neuropsychopharmacol 15(7):907–917

    Article  CAS  PubMed  Google Scholar 

  28. Didriksen M, Kreilgaard M, Arnt J (2006) Sertindole, in contrast to clozapine and olanzapine, does not disrupt water maze performance after acute or chronic treatment. Eur J Pharmacol 542(1–3):108–115

    Article  CAS  PubMed  Google Scholar 

  29. Pridan S, Swartz M, Baruch Y, Tadger S, Plopski I, Barak Y (2015) Effectiveness and safety of clozapine in elderly patients with chronic resistant schizophrenia. Int Psychogeriatr 27(1):131–134

    Article  PubMed  Google Scholar 

  30. Cheng CY, Hong CJ, Tsai SJ (2005) Effects of subchronic clozapine administration on serum glucose, cholesterol and triglyceride levels, and body weight in male BALB/c mice. Life Sci 76(19):2269–2273

    Article  CAS  PubMed  Google Scholar 

  31. Boyda HN, Tse L, Procyshyn RM, Honer WG, Barr AM (2010) Preclinical models of antipsychotic drug-induced metabolic side effects. Trends Pharmacol Sci 31(10):484–497

    Article  CAS  PubMed  Google Scholar 

  32. Kuester RK, Waalkes MP, Goering PL, Fisher BL, McCuskey RS, Sipes IG (2002) Differential hepatotoxicity induced by cadmium in Fischer 344 and Sprague–Dawley rats. Toxicol Sci 65(1):151–159

    Article  CAS  PubMed  Google Scholar 

  33. Zlatković J, Todorović N, Tomanović N, Bošković M, Djordjević S, Lazarević-Pašti T, Bernardi RE, Djurdjević A, Filipović D (2014) Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: a histopathological study. Eur J Pharm Sci 59:20–30

    Article  PubMed  Google Scholar 

  34. Yuan HY, Liang HX, Liang GR, Zhang GX, Li HD (2008) Effects of clozapine administration on body weight, glucose tolerance, blood glucose concentrations, plasma lipids, and insulin in male C57BL/6 mice: a parallel controlled study. Curr Ther Res Clin Exp 69(2):142–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lauterbach EC, Mendez MF (2011) Psychopharmacological neuroprotection in neurodegenerative diseases, part III: criteria-based assessment: a report of the ANPA committee on research. J Neuropsychiatry Clin Neurosci 23(3):242–260

    Article  CAS  PubMed  Google Scholar 

  36. Burgess BL, McIsaac SA, Naus KE, Chan JY, Tansley GH, Yang J, Miao F, Ross CJ, van Eck M, Hayden MR, van Nostrand W, St George-Hyslop P, Westaway D, Wellington CL (2006) Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer’s disease mouse models with abundant A beta in plasma. Neurobiol Dis 24(1):114–127

    Article  CAS  PubMed  Google Scholar 

  37. Currais A, Prior M, Dargusch R, Armando A, Ehren J, Schubert D, Quehenberger O, Maher P (2014) Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer’s disease transgenic mice. Aging Cell 13(2):379–390

    Article  CAS  PubMed  Google Scholar 

  38. Menegon A, Bonanomi D, Albertinazzi C, Lotti F, Ferrari G, Kao HT, Benfenati F, Baldelli P, Valtorta F (2006) Protein kinase A-mediated synapsin I phosphorylation is a central modulator of Ca2 + −dependent synaptic activity. J Neurosci 26(45):11670–11681

    Article  CAS  PubMed  Google Scholar 

  39. Verstegen AM, Tagliatti E, Lignani G, Marte A, Stolero T, Atias M, Corradi A, Valtorta F, Gitler D, Onofri F, Fassio A, Benfenati F (2014) Phosphorylation of synapsin I by cyclin-dependent kinase-5 sets the ratio between the resting and recycling pools of synaptic vesicles at hippocampal synapses. J Neurosci 34(21):7266–7280

    Article  CAS  PubMed  Google Scholar 

  40. Vingtdeux V, Chandakkar P, Zhao H, d’Abramo C, Davies P, Marambaud P (2011) Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation. FASEB J 25(1):219–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Won JS, Im YB, Kim J, Singh AK, Singh I (2010) Involvement of AMP-activated-protein-kinase (AMPK) in neuronal amyloidogenesis. Biochem Biophys Res Commun 399(4):487–491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tschäpe JA, Hammerschmied C, Mühlig-Versen M, Athenstaedt K, Daum G, Kretzschmar D (2002) The neurodegeneration mutant löchrig interferes with cholesterol homeostasis and Appl processing. EMBO J 21(23):6367–6376

    Article  PubMed  PubMed Central  Google Scholar 

  43. Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, Wang L, Blesch A, Kim A, Conner JM, Rockenstein E, Chao MV, Koo EH, Geschwind D, Masliah E, Chiba AA, Tuszynski MH (2009) Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 15(3):331–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Castello NA, Nguyen MH, Tran JD, Cheng D, Green KN, LaFerla FM (2014) 7,8-Dihydroxyflavone, a small molecule TrkB agonist, improves spatial memory and increases thin spine density in a mouse model of Alzheimer disease-like neuronal loss. PLoS One 9(3):e91453

    Article  PubMed  PubMed Central  Google Scholar 

  45. Zhang Z, Liu X, Schroeder JP, Chan CB, Song M, Yu SP, Weinshenker D, Ye K (2014) 7,8-Dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 39(3):638–650

    Article  PubMed  Google Scholar 

  46. Psotta L, Rockahr C, Gruss M, Kirches E, Braun K, Lessmann V, Bock J, Endres T (2015) Impact of an additional chronic BDNF reduction on learning performance in an Alzheimer mouse model. Front Behav Neurosci 9:58

    Article  PubMed  PubMed Central  Google Scholar 

  47. Bai O, Chlan-Fourney J, Bowen R, Keegan D, Li XM (2003) Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs. J Neurosci Res 71(1):127–131

    Article  CAS  PubMed  Google Scholar 

  48. Park SW, Lee CH, Lee JG, Lee SJ, Kim NR, Choi SM, Kim YH (2009) Differential effects of ziprasidone and haloperidol on immobilization stress-induced mRNA BDNF expression in the hippocampus and neocortex of rats. J Psychiatr Res 43(3):274–281

    Article  PubMed  Google Scholar 

  49. Pandya CD, Kutiyanawalla A, Pillai A (2013) BDNF-TrkB signaling and neuroprotection in schizophrenia. Asian J Psychiatr 6(1):22–28

    Article  PubMed  Google Scholar 

  50. Huang W, Cao J, Liu X, Meng F, Li M, Chen B, Zhang J (2015) AMPK plays a dual role in regulation of CREB/BDNF pathway in mouse primary hippocampal cells. J Mol Neurosci 56(4):782–788

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, and Republic of Korea (A121737).

Conflict of interest

The authors have no potential conflict of interest to declare.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Dongguk University, Gyeonggi-do, 10326, Republic of Korea

    Yura Choi & Seung Tack Oh

  2. Dongguk University Research Institute of Bio-Medi Integration, Sangyoung-Bio, Biomedi-Campus, Dongguk-ro 32, Goyang-si, Gyeonggi-do, 10326, Republic of Korea

    Ha Jin Jeong & Songhee Jeon

  3. Department of Neuropsychiatry, Graduate School of Oriental Medicine, Dongguk University, Gyeongju, 38066, Republic of Korea

    Quan Feng Liu & Byung-Soo Koo

  4. Department of Child Psychiatry, National Center for Child and Adolescent Psychiatry, Seoul National Hospital, Seoul, 04933, Republic of Korea

    Yeni Kim

  5. Department of Neuropsychiatry, Dongguk University International Hospital, Dongguk University Medical School, Gyeonggi-do, 10326, Republic of Korea

    In-Won Chung & Yong Sik Kim

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  1. Yura Choi
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  2. Ha Jin Jeong
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Correspondence to Yong Sik Kim or Songhee Jeon.

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Choi, Y., Jeong, H.J., Liu, Q.F. et al. Clozapine Improves Memory Impairment and Reduces Aβ Level in the Tg-APPswe/PS1dE9 Mouse Model of Alzheimer’s Disease. Mol Neurobiol 54, 450–460 (2017). https://doi.org/10.1007/s12035-015-9636-x

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  • DOI: https://doi.org/10.1007/s12035-015-9636-x

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