Molecular Neurobiology

, Volume 56, Issue 7, pp 4980–4987 | Cite as

Effect of Exercise and Aβ Protein Infusion on Long-Term Memory-Related Signaling Molecules in Hippocampal Areas

  • Karim A. AlkadhiEmail author
  • An T. Dao


Alzheimer’s disease (AD) results from over-production and aggregation of β-amyloid (Aβ) oligopeptides in the brain. The benefits of regular physical exercise are now recognized in a variety of disorders including AD. In order to understand the effect of exercise at the molecular level, we studied the impact of exercise on long-term memory-related signaling molecules in an AD rat model. The rat model of AD (AD rat) was produced by 14-day osmotic pump infusion of i.c.v. 250 pmol/day Aβ1–42. The effects of 4 weeks of regular rodent treadmill exercise on the protein levels of CREB, CaMKVI, and MAPK-ERK1/2 in this model were determined by immunoblot analysis in the CA1 and dentate gyrus (DG) areas of the hippocampus, which is among the first brain structures impacted by AD. Aβ infusion caused marked reductions in the basal protein levels of CaMKVI and phosphorylated CREB without significantly affecting total CREB levels in both CA1 and DG areas. As predicted, our exercise regimen totally prevented these effects in the brains of exercised AD rats. Surprisingly, however, neither Aβ infusion nor exercise had any significant effect on the levels of phosphorylated or total ERK in the CA1 and DG areas. Additionally, exercise did not increase any of these molecules in healthy normal rats, which indicated a protective effect of exercise. These findings suggest that CaMKIV is likely a major kinase for phosphorylation of CREB. Therefore, regular exercise is highly effective in preventing the effects of AD even at the molecular level in both areas of the hippocampus. Considering the well-known resistance of the DG area to insults relative to area CA1, the present findings revealed similar molecular vulnerability of the two areas to AD pathology.


Rat AD model Amyloid-beta Regular exercise Signaling molecules ERK1/2 CaMKIV 


  1. 1.
    Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35:605–623PubMedGoogle Scholar
  2. 2.
    Kang H, Sun LD, Atkins CM, Soderling TR, Wilson MA, Tonegawa S (2001) An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory. Cell 106:771–783PubMedGoogle Scholar
  3. 3.
    Chow FA, Anderson KA, Noeldner PK, Means AR (2005) The autonomous activity of calcium/calmodulin-dependent protein kinase IV is required for its role in transcription. J Biol Chem 280:20530–20538PubMedGoogle Scholar
  4. 4.
    Ho N, Liauw JA, Blaeser F, Wei F, Hanissian S, Muglia LM, Wozniak DF, Nardi A et al (2000) Impaired synaptic plasticity and cAMP response element-binding protein activation in Ca2+/calmodulin-dependent protein kinase type IV/Gr-deficient mice. J Neurosci 20:6459–6472PubMedPubMedCentralGoogle Scholar
  5. 5.
    Limbäck-Stokin K, Korzus E, Nagaoka-Yasuda R, Mayford M (2004) Nuclear calcium/calmodulin regulates memory consolidation. J Neurosci 24:10858–10867PubMedPubMedCentralGoogle Scholar
  6. 6.
    Lee E, Son H (2009) Adult hippocampal neurogenesis and related neurotrophic factors. BMB Rep 42:239–244PubMedGoogle Scholar
  7. 7.
    Fukushima H, Maeda R, Suzuki R, Suzuki A, Nomoto M, Toyoda H, Wu LJ, Xu H et al (2008) Upregulation of calcium/calmodulin-dependent protein kinase IV improves memory formation and rescues memory loss with aging. J Neurosci 28:9910–9919PubMedPubMedCentralGoogle Scholar
  8. 8.
    Pittenger C, Kandel E (1998) A genetic switch for long-term memory. C R Acad Sci III 321:91–96PubMedGoogle Scholar
  9. 9.
    Alberini CM (2009) Transcription factors in long-term memory and synaptic plasticity. Physiol Rev 89:121–145PubMedGoogle Scholar
  10. 10.
    Kida S (2012) A functional role for CREB as a positive regulator of memory formation and LTP. Exp Neurobiol 21:136–140PubMedPubMedCentralGoogle Scholar
  11. 11.
    Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821–861PubMedGoogle Scholar
  12. 12.
    Du K, Asahara H, Jhala US, Wagner BL, Montminy M (2000) Characterization of a CREB gain-of-function mutant with constitutive transcriptional activity in vivo. Mol Cell Biol 20:4320–4327PubMedPubMedCentralGoogle Scholar
  13. 13.
    Barco A, Patterson SL, Alarcon JM, Gromova P, Mata-Roig M, Morozov A, Kandel ER (2005) Gene expression profiling of facilitated L-LTP in VP16-CREB mice reveals that BDNF is critical for the maintenance of LTP and its synaptic capture. Neuron 48:123–137PubMedGoogle Scholar
  14. 14.
    Fan N, Yang H, Zhang J, Chen C (2010) Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivo Delta9-THC exposure-impaired hippocampal synaptic plasticity. J Neurochem 112:691–702PubMedGoogle Scholar
  15. 15.
    Middei S, Houeland G, Cavallucci V, Ammassari-Teule M, D'Amelio M, Marie H (2013) CREB is necessary for synaptic maintenance and learning-induced changes of the ampa receptor GluA1 subunit. Hippocampus 23:488–499PubMedGoogle Scholar
  16. 16.
    Jancic D, Lopez de Armentia M, Valor LM, Olivares R, Barco A (2009) Inhibition of cAMP response element-binding protein reduces neuronal excitability and plasticity, and triggers neurodegeneration. Cereb Cortex 19:2535–2547PubMedGoogle Scholar
  17. 17.
    Giovannini MG (2006) The role of the extracellular signal-regulated kinase pathway in memory encoding. Rev Neurosci 17:619–634PubMedGoogle Scholar
  18. 18.
    Xia Z, Storm DR (2012) Role of signal transduction crosstalk between adenylyl ncyclase and MAP kinase in hippocampus-dependent memory. Learn Mem 19:369–374PubMedPubMedCentralGoogle Scholar
  19. 19.
    Kamei H, Nagai T, Nakano H, Togan Y, Takayanagi M, Takahashi K, Kobayashi K, Yoshida S et al (2006) Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice. Biol Psychiatry 59:75–84PubMedGoogle Scholar
  20. 20.
    Huang CH, Chiang YW, Liang KC, Thompson RF, Liu IY (2010) Extra-cellular signal-regulated kinase 1/2 (ERK1/2) activated in the hippocampal CA1 neurons is critical for retrieval of auditory trace fear memory. Br Res 1326:143–151Google Scholar
  21. 21.
    Roskoski R Jr (2012) ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res 66:105–143PubMedGoogle Scholar
  22. 22.
    Mao L, Tang Q, Samdani S, Liu Z, Wang JQ (2004) Regulation of MAPK/ERK phosphorylation via ionotropic glutamate receptors in cultured rat striatal neurons. Eur J Neurosci 19:1207–1216PubMedGoogle Scholar
  23. 23.
    Tiraboschi E, Tardito D, Kasahara J, Moraschi S, Pruneri P, Gennarelli M, Racagni G, Popoli M (2004) Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades. Neuropsychopharmacology 29:1831–1840PubMedGoogle Scholar
  24. 24.
    English JD, Sweatt JD (1997) A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation. J Biol Chem 272:19103–19106PubMedGoogle Scholar
  25. 25.
    Dao AT, Zagaar MA, Levine AT, Salim S, Eriksen JL, Alkadhi KA (2013) Treadmill exercise prevents learning and memory impairment in Alzheimer’s disease-like pathology. Curr Alzheimer Res 10:507–515PubMedPubMedCentralGoogle Scholar
  26. 26.
    Dao AT, Zagaar MA, Salim S, Eriksen JL, Alkadhi KA (2014) Regular exercise prevents non-cognitive disturbances in a rat model of Alzheimer’s disease. Int J Neuropsychopharmacol 17:593–602PubMedGoogle Scholar
  27. 27.
    Dao AT, Zagaar MA, Alkadhi KA (2015) Moderate treadmill exercise protects synaptic plasticity of the dentate gyrus and related signaling cascade in a rat model of Alzheimer’s disease. Mol Neurobiol 52:1067–1076PubMedGoogle Scholar
  28. 28.
    Kandel ER (2012) The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain 5:14PubMedPubMedCentralGoogle Scholar
  29. 29.
    Ran I, Laplante I, Lacaille JC (2012) CREB-dependent transcriptional control and quantal changes in persistent long-term potentiation in hippocampal interneurons. J Neurosci 32:6335–6350PubMedPubMedCentralGoogle Scholar
  30. 30.
    Alkadhi KA, Alzoubi KH, Srivareerat M, Tran TT (2011) Chronic psychosocial stress exacerbates impairment of synaptic plasticity in β-amyloid rat model of Alzheimer’s disease: prevention by nicotine. Curr Alzheimer Res 8:718–731PubMedGoogle Scholar
  31. 31.
    Miyamoto E (2006) Molecular mechanism of neuronal plasticity: induction and maintenance of long-term potentiation in the hippocampus. J Pharmacol Sci 100:433–442PubMedGoogle Scholar
  32. 32.
    Kasahara J, Fukunaga K, Miyamoto E (2001) Activation of calcium/calmodulin-dependent protein kinase IV in long term potentiation in the rat hippocampal CA1 region. J Biol Chem 276:24044–24050PubMedGoogle Scholar
  33. 33.
    Smolen P, Baxter DA, Byrne JH (2006) A model of the roles of essential kinases in the induction and expression of late long-term potentiation. Biophys J 90:2760–2775PubMedPubMedCentralGoogle Scholar
  34. 34.
    Peng S, Zhang Y, Zhang J, Wang H, Ren B (2010) ERK in learning and memory: a review of recent research. Int JMol Sci 11:222–232Google Scholar
  35. 35.
    Pugazhenthi S, Wang M, Pham S, Sze CI, Eckman CB (2011) Downregulation of CREB expression in Alzheimer’s brain and in Abeta-treated rat hippocampal neurons. Mol Neurodegener 6:60PubMedPubMedCentralGoogle Scholar
  36. 36.
    Ljungberg MC, Ali YO, Zhu J, Wu CS, Oka K, Zhai RG, Lu HC (2012) CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy. Human Mol Gen 21:251–267Google Scholar
  37. 37.
    Jin N, Qian W, Yin X, Zhang L, Iqbal K, Grundke-Iqbal I, Gong CX, Liu F (2013) CREB regulates the expression of neuronal glucose transporter 3: a possible mechanism related to impaired brain glucose uptake in Alzheimer’s disease. Nucleic Acids Res 41:3240–3256PubMedPubMedCentralGoogle Scholar
  38. 38.
    Dao AT, Zagaar MA, Levine AT, Alkadhi KA (2016) Comparison of the effect of exercise on late-phase LTP of the dentate gyrus and CA1 of Alzheimer’s disease model. Mol Neurobiol 53:6859–6868PubMedGoogle Scholar
  39. 39.
    Vaynman S, Ying Z, Gomez-Pinilla F (2003) Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience 122:647–657PubMedGoogle Scholar
  40. 40.
    Chen MJ, Russo-Neustadt AA (2009) Running exercise-induced up-regulation of hippocampal brain-derived neurotrophic factor is CREB-dependent. Hippocampus 19:962–972PubMedPubMedCentralGoogle Scholar
  41. 41.
    Arrazola MS, Varela-Nallar L, Colombres M, Toledo EM, Cruzat F, Pavez L, Assar R, Aravena A et al (2009) Calcium/calmodulin-dependent protein kinase type IV is a target gene of the Wnt/beta-catenin signaling pathway. J Cell Physiol 221:658–667PubMedGoogle Scholar
  42. 42.
    Zagaar M, Dao A, Levine A, Alhaider I, Alkadhi K (2013) Regular exercise prevents sleep deprivation associated impairment of long-term memory and synaptic plasticity in the CA1 area of the hippocampus. Sleep 36:751–761PubMedPubMedCentralGoogle Scholar
  43. 43.
    Zagaar M, Dao A, Alhaider I, Alkadhi K (2013) Regular treadmill exercise prevents sleep deprivation-induced disruption of synaptic plasticity and associated signaling cascade in the dentate gyrus. Mol Cell Neurosci 56:375–383PubMedGoogle Scholar
  44. 44.
    Cassilhas RC, Lee KS, Fernandes J, Oliveira MG, Tufik S, Meeusen R, de Mello MT (2012) Spatial memory is improved by aerobic and resistance exercise through divergent molecular mechanisms. Neuroscience 202:309–317PubMedGoogle Scholar
  45. 45.
    Bechara RG, Kelly AM (2013) Exercise improves object recognition memory and induces BDNF expression and cell proliferation in cognitively enriched rats. Behav Br Res 245:96–100Google Scholar
  46. 46.
    Zhao WQ, Ravindranath L, Mohamed AS, Zohar O, Chen GH, Lyketsos CG, Etcheberrigaray R, Alkon DL (2002) MAP kinase signaling cascade dysfunction specific to Alzheimer’s disease in fibroblasts. Neurobiol Dis 11:156–163Google Scholar
  47. 47.
    Shen J, Maruyama IN (2012) Brain-derived neurotrophic factor receptor TrkB exists as a preformed dimer in living cells. J Mol Signal 7:2PubMedPubMedCentralGoogle Scholar
  48. 48.
    Hu Q, Yu B, Chen Q, Wang Y, Ling Y, Sun S, Shi Y, Zhou C (2018) Effect of Linguizhugan decoction on neuroinflammation and expression disorder of the amyloid β-related transporters RAGE and LRP-1 in a rat model of Alzheimer’s disease. Mol Med Rep 17:827–834PubMedGoogle Scholar
  49. 49.
    Lv C, Wang L, Liu X, Yan S, Yan SS, Wang Y, Zhang W (2015) Multi-faced neuroprotective effects of geniposide depending on the RAGE-mediated signaling in an Alzheimer mouse model. Neuropharmacology 89:175–184PubMedGoogle Scholar
  50. 50.
    Hsu JC, Zhang Y, Takagi N, Gurd JW, Wallace MC, Zhang L, Eubanks JH (1998) Decreased expression and functionality of NMDA receptor complexes persist in the CA1, but not in the dentate gyrus after transient cerebral ischemia. J Cereb Blood Flow Metab 18:768–775PubMedGoogle Scholar
  51. 51.
    Yao H, Huang YH, Liu ZW, Wan Q, Ding AS, Zhao B, Fan M, Wang FZ (1998) The different responses to anoxia in cultured CA1 and DG neurons from newborn rats. Acta Phys Sin 50:61–66Google Scholar
  52. 52.
    Gerges NZ, Alkadhi KA (2004) Hypothyroidism impairs late LTP in CA1 region but not in dentate gyrus of the intact rat hippocampus: MAPK involvement. Hippocampus 14:40–45PubMedGoogle Scholar
  53. 53.
    Alzoubi KH, Aleisa AM, Alkadhi KA (2005) Impairment of long-term potentiation in the CA1, but not dentate gyrus, of the hippocampus in obese Zucker rats: role of calcineurin and phosphorylated CaMKII. J Mol Neurosci 27:337–346PubMedGoogle Scholar
  54. 54.
    Sawada M, Sawamoto K (2013) Mechanisms of neurogenesis in the normal and injured adult brain. Keio J Med 62:13–28PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Pharmacological and Pharmaceutical Sciences, College of PharmacyUniversity of HoustonHoustonUSA

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