Skip to main content

Advertisement

Log in

Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Aβ and tau pathologies in 3xTg-AD mice

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

In addition to the occurrence of numerous neurofibrillary tangles and Aβ plaques, neurogenesis and neuronal plasticity are markedly altered in Alzheimer disease (AD). Although the most popular therapeutic approach has been to inhibit neurodegeneration, another is to promote neurogenesis and neuronal plasticity by utilizing the regenerative capacity of the brain. Here we show that, in a transgenic mouse model of AD, 3xTg-AD mice, there was a marked deficit in neurogenesis and neuroplasticity, which occured before the formation of any neurofibrillary tangles or Aβ plaques and was associated with cognitive impairment. Furthermore, peripheral administration of Peptide 6, an 11-mer, which makes an active region of ciliary neurotrophic factor (CNTF, amino acid residues 146–156), restored cognition by enhancing neurogenesis and neuronal plasticity in these mice. Although this treatment had no detectable effect on Aβ and tau pathologies in 9-month animals, it enhanced neurogenesis in dentate gyrus, reduced ectopic birth in the granular cell layer, and increased neuronal plasticity in the hippocampus and cerebral cortex. These findings, for the first time, demonstrate the possibility of therapeutic treatment of AD and related disorders by peripheral administration of a peptide corresponding to a biologically active region of CNTF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Aberg MA, Aberg ND, Hedbacker H, Oscarsson J, Eriksson PS (2000) Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J Neurosci 20:2896–2903

    CAS  PubMed  Google Scholar 

  2. Abrous DN, Wojtowics JM (2008) Neurogenesis and hippocampal memory system. In: Adult neurogenesis. Cold Spring Harbor Press, New York

  3. ACTSG (1996) A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group. Neurology 46:1244–1249

    Google Scholar 

  4. Aimone JB, Wiles J, Gage FH (2006) Potential role for adult neurogenesis in the encoding of time in new memories. Nat Neurosci 9:723–727

    Article  CAS  PubMed  Google Scholar 

  5. Anderson MF, Aberg MA, Nilsson M, Eriksson PS (2002) Insulin-like growth factor-I and neurogenesis in the adult mammalian brain. Brain Res Dev Brain Res 134:115–122

    Article  CAS  PubMed  Google Scholar 

  6. Artero S, Tierney MC, Touchon J, Ritchie K (2003) Prediction of transition from cognitive impairment to senile dementia: a prospective, longitudinal study. Acta Psychiatr Scand 107:390–393

    Article  CAS  PubMed  Google Scholar 

  7. Arthur CP, Stowell MH (2007) Structure of synaptophysin: a hexameric MARVEL-domain channel protein. Structure 15:707–714

    Article  CAS  PubMed  Google Scholar 

  8. Bensadoun A, Weinstein D (1976) Assay of proteins in the presence of interfering materials. Anal Biochem 70:241–250

    Article  CAS  PubMed  Google Scholar 

  9. Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45:675–688

    Article  CAS  PubMed  Google Scholar 

  10. Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Muller FJ, Loring JF et al (2009) Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci USA 106:13594–13599

    Article  CAS  PubMed  Google Scholar 

  11. Boissonneault V, Filali M, Lessard M, Relton J, Wong G, Rivest S (2009) Powerful beneficial effects of macrophage colony-stimulating factor on beta-amyloid deposition and cognitive impairment in Alzheimer’s disease. Brain 132:1078–1092

    Article  PubMed  Google Scholar 

  12. Bredt DS, Nicoll RA (2003) AMPA receptor trafficking at excitatory synapses. Neuron 40:361–379

    Article  CAS  PubMed  Google Scholar 

  13. Butte MJ (2001) Neurotrophic factor structures reveal clues to evolution, binding, specificity and receptor activation. Cell Mol Life Sci 58:1003–1013

    Article  CAS  PubMed  Google Scholar 

  14. Cameron HA, McKay RD (1999) Restoring production of hippocampal neurons in old age. Nat Neurosci 2:894–897

    Article  CAS  PubMed  Google Scholar 

  15. Chevallier NL, Soriano S, Kang DE, Masliah E, Hu G, Koo EH (2005) Perturbed neurogenesis in the adult hippocampus associated with presenilin-1 A246E mutation. Am J Pathol 167:151–159

    CAS  PubMed  Google Scholar 

  16. Chohan MO, Li B, Blanchard J, Tung YC, Heaney AT, Rabe A et al (2009) Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide. Neurobiol Aging (in press)

  17. Clark RE, Zola SM, Squire LR (2000) Impaired recognition memory in rats after damage to the hippocampus. J Neurosci 20:8853–8860

    CAS  PubMed  Google Scholar 

  18. Collingridge GL, Isaac JT, Wang YT (2004) Receptor trafficking and synaptic plasticity. Nat Rev Neurosci 5:952–962

    Article  CAS  PubMed  Google Scholar 

  19. DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464

    Article  CAS  PubMed  Google Scholar 

  20. DeKosky ST, Scheff SW, Styren SD (1996) Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration 5:417–421

    Article  CAS  PubMed  Google Scholar 

  21. Demars M, Hu YS, Gadadhar A, Lazarov O (2010) Impaired neurogenesis is an early event in the etiology of familial Alzheimer’s disease in transgenic mice. J Neurosci Res 88:2103–2117

    Article  CAS  PubMed  Google Scholar 

  22. Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG (2004) Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience 127:601–609

    Article  CAS  PubMed  Google Scholar 

  23. Donovan MH, Yazdani U, Norris RD, Games D, German DC, Eisch AJ (2006) Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer’s disease. J Comp Neurol 495:70–83

    Article  PubMed  Google Scholar 

  24. Ennaceur A (2010) One-trial objects recognition in rats and mice: methodological and theoretical issues. Behav Brain Res (in press)

  25. Ennaceur A, Aggleton JP (1997) The effects of neurotoxic lesions of the perirhinal cortex combined to fornix transection on object recognition memory in the rat. Behav Brain Res 88:181–193

    Article  CAS  PubMed  Google Scholar 

  26. Ennaceur A, Neave N, Aggleton JP (1997) Spontaneous object recognition and object location memory in rats: the effects of lesions in the cingulate cortices, the medial prefrontal cortex the cingulum bundle and the fornix. Exp Brain Res 113:509–519

    Article  CAS  PubMed  Google Scholar 

  27. Garcia P, Youssef I, Utvik JK, Florent-Bechard S, Barthelemy V, Malaplate-Armand C et al (2010) Ciliary neurotrophic factor cell-based delivery prevents synaptic impairment and improves memory in mouse models of Alzheimer’s disease. J Neurosci 30:7516–7527

    Article  CAS  PubMed  Google Scholar 

  28. Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885–890

    Article  CAS  PubMed  Google Scholar 

  29. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917

    Article  CAS  PubMed  Google Scholar 

  30. Haughey NJ, Liu D, Nath A, Borchard AC, Mattson MP (2002) Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture by amyloid beta-peptide: implications for the pathogenesis of Alzheimer’s disease. Neuromolecular Med 1:125–135

    Article  CAS  PubMed  Google Scholar 

  31. Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP (2002) Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis in models of Alzheimer’s disease. J Neurochem 83:1509–1524

    Article  CAS  PubMed  Google Scholar 

  32. Inoue M, Karita H, Nakayama C, Noguchi H (1997) Construction and characterization of ciliary neurotrophic factor (CNTF) antagonists: microenvironmental difference in the CNTF receptor between rat and chicken cells for recognizing the D1 cap region. J Neurochem 69:95–101

    Article  CAS  PubMed  Google Scholar 

  33. Janz R, Sudhof TC, Hammer RE, Unni V, Siegelbaum SA, Bolshakov VY (1999) Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin. I Neuron 24:687–700

    Article  CAS  Google Scholar 

  34. Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC et al (2004) Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci USA 101:343–347

    Article  CAS  PubMed  Google Scholar 

  35. Jin K, Xie L, Childs J, Sun Y, Mao XO, Logvinova A et al (2003) Cerebral neurogenesis is induced by intranasal administration of growth factors. Ann Neurol 53:405–409

    Article  CAS  PubMed  Google Scholar 

  36. Karishma KK, Herbert J (2002) Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat promotes survival of newly formed neurons and prevents corticosterone-induced suppression. Eur J Neurosci 16:445–453

    Article  CAS  PubMed  Google Scholar 

  37. Kee N, Teixeira CM, Wang AH, Frankland PW (2007) Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 10:355–362

    Article  CAS  PubMed  Google Scholar 

  38. Kempermann G, Kuhn HG, Gage FH (1998) Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci 18:3206–3212

    CAS  PubMed  Google Scholar 

  39. Kim KS, Miller DL, Sapienza VJ, Chen C-M J, Bai C, Grundke-Iqbal I et al (1988) Production and characterization of monoclonal antibodies reactive to synthetic cerebrovascular amyloid peptide. Neurosci Res Commun 2:121–130

    CAS  Google Scholar 

  40. Kuhn HG, Dickinson-Anson H, Gage FH (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16:2027–2033

    CAS  PubMed  Google Scholar 

  41. Kuhn HG, Winkler J, Kempermann G, Thal LJ, Gage FH (1997) Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J Neurosci 17:5820–5829

    CAS  PubMed  Google Scholar 

  42. Leuner B, Gould E, Shors TJ (2006) Is there a link between adult neurogenesis and learning? Hippocampus 16:216–224

    Article  PubMed  Google Scholar 

  43. Li B, Yamamori H, Tatebayashi Y, Shafit-Zagardo B, Tanimukai H, Chen S et al (2008) Failure of neuronal maturation in Alzheimer disease dentate gyrus. J Neuropathol Exp Neurol 67:78–84

    Article  CAS  PubMed  Google Scholar 

  44. Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, Riddle DR (2001) Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 107:603–613

    Article  CAS  PubMed  Google Scholar 

  45. Lledo PM, Alonso M, Grubb MS (2006) Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7:179–193

    Article  CAS  PubMed  Google Scholar 

  46. Malinow R, Malenka RC (2002) AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 25:103–126

    Article  CAS  PubMed  Google Scholar 

  47. Masliah E, Mallory M, Hansen L, DeTeresa R, Alford M, Terry R (1994) Synaptic and neuritic alterations during the progression of Alzheimer’s disease. Neurosci Lett 174:67–72

    Article  CAS  PubMed  Google Scholar 

  48. Mayo W, George O, Darbra S, Bouyer JJ, Vallee M, Darnaudery M et al (2003) Individual differences in cognitive aging: implication of pregnenolone sulfate. Prog Neurobiol 71:43–48

    Article  CAS  PubMed  Google Scholar 

  49. McDonald HY, Wojtowicz JM (2005) Dynamics of neurogenesis in the dentate gyrus of adult rats. Neurosci Lett 385:70–75

    Article  CAS  PubMed  Google Scholar 

  50. McDonald NQ, Panayotatos N, Hendrickson WA (1995) Crystal structure of dimeric human ciliary neurotrophic factor determined by MAD phasing. EMBO J 14:2689–2699

    CAS  PubMed  Google Scholar 

  51. Mitchell JB, Laiacona J (1998) The medial frontal cortex and temporal memory: tests using spontaneous exploratory behaviour in the rat. Behav Brain Res 97:107–113

    Article  CAS  PubMed  Google Scholar 

  52. Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R (2005) Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev 19:1432–1437

    Article  CAS  PubMed  Google Scholar 

  53. Morgan D, Munireddy S, Alamed J, DeLeon J, Diamond DM, Bickford P et al (2008) Apparent behavioral benefits of tau overexpression in P301L tau transgenic mice. J Alzheimers Dis 15:605–614

    CAS  PubMed  Google Scholar 

  54. Morris RG, Garrud P, Rawlins JN, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683

    Article  CAS  PubMed  Google Scholar 

  55. Nacher J, Alonso-Llosa G, Rosell DR, McEwen BS (2003) NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol Aging 24:273–284

    Article  CAS  PubMed  Google Scholar 

  56. Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM et al (2009) Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 15:331–337

    Article  CAS  PubMed  Google Scholar 

  57. Neves G, Cooke SF, Bliss TV (2008) Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev Neurosci 9:65–75

    Article  CAS  PubMed  Google Scholar 

  58. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R et al (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421

    Article  CAS  PubMed  Google Scholar 

  59. Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167

    Article  CAS  PubMed  Google Scholar 

  60. Rai KS, Hattiangady B, Shetty AK (2007) Enhanced production and dendritic growth of new dentate granule cells in the middle-aged hippocampus following intracerebroventricular FGF-2 infusions. Eur J Neurosci 26:1765–1779

    Article  PubMed  Google Scholar 

  61. Rao MS, Hattiangady B, Shetty AK (2006) The window and mechanisms of major age-related decline in the production of new neurons within the dentate gyrus of the hippocampus. Aging Cell 5:545–558

    Article  CAS  PubMed  Google Scholar 

  62. Riedel G, Micheau J, Lam AG, Roloff EL, Martin SJ, Bridge H et al (1999) Reversible neural inactivation reveals hippocampal participation in several memory processes. Nat Neurosci 2:898–905

    Article  CAS  PubMed  Google Scholar 

  63. Rousseau F, Gauchat JF, McLeod JG, Chevalier S, Guillet C, Guilhot F et al (2006) Inactivation of cardiotrophin-like cytokine, a second ligand for ciliary neurotrophic factor receptor, leads to cold-induced sweating syndrome in a patient. Proc Natl Acad Sci USA 103:10068–10073

    Article  CAS  PubMed  Google Scholar 

  64. Sanchez-Ramos J, Song S, Sava V, Catlow B, Lin X, Mori T et al (2009) Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer’s mice. Neuroscience 163:55–72

    Article  CAS  PubMed  Google Scholar 

  65. Sargolini F, Roullet P, Oliverio A, Mele A (2003) Effects of intra-accumbens focal administrations of glutamate antagonists on object recognition memory in mice. Behav Brain Res 138:153–163

    Article  CAS  PubMed  Google Scholar 

  66. Sze CI, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ (1997) Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol 56:933–944

    Article  CAS  PubMed  Google Scholar 

  67. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580

    Article  CAS  PubMed  Google Scholar 

  68. Trejo JL, Carro E, Torres-Aleman I (2001) Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci 21:1628–1634

    CAS  PubMed  Google Scholar 

  69. Tsai KJ, Tsai YC, Shen CK (2007) G-CSF rescues the memory impairment of animal models of Alzheimer’s disease. J Exp Med 204:1273–1280

    Article  CAS  PubMed  Google Scholar 

  70. van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034

    Article  PubMed  Google Scholar 

  71. Verret L, Trouche S, Zerwas M, Rampon C (2007) Hippocampal neurogenesis during normal and pathological aging. Psychoneuroendocrinology 32(Suppl 1):S26–S30

    Google Scholar 

  72. Wang JM, Singh C, Liu L, Irwin RW, Chen S, Chung EJ et al (2010) Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 107:6498–6503

    Article  CAS  PubMed  Google Scholar 

  73. Welsh KA, Butters N, Hughes JP, Mohs RC, Heyman A (1992) Detection and staging of dementia in Alzheimer’s disease. Use of the neuropsychological measures developed for the Consortium to Establish a Registry for Alzheimer’s Disease. Arch Neurol 49:448–452

    CAS  PubMed  Google Scholar 

  74. Wen PH, Hof PR, Chen X, Gluck K, Austin G, Younkin SG et al (2004) The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice. Exp Neurol 188:224–237

    Article  CAS  PubMed  Google Scholar 

  75. West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482–497

    Article  CAS  PubMed  Google Scholar 

  76. Windisch M, Gschanes A, Hutter-Paier B (1998) Neurotrophic activities and therapeutic experience with a brain derived peptide preparation. J Neural Transm Suppl 53:289–298

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Prof. Dr. Peter R. Schreiner and Dr. Heike Hausmann, Institute of Organic Chemistry, University of Giessen (Germany) for the NMR characterization. ESI–MS analysis for Peptide 6 by Dr. David Bolton is gratefully acknowledged. We are grateful to Dr. George Merz for confocal assistance and to Mrs. Janet Murphy for secretarial assistance. This work was supported in part by the New York State Office of People With Developmental Disabilities; EVER NeuroPharma GmbH, Unterach, Austria; and the T.L.L. Temple Foundation Discovery Award for Alzheimer Disease Research, the Alzheimer Association, Chicago, IL.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Inge Grundke-Iqbal.

Additional information

J. Blanchard carried out most of the work, i.e. treatment of the mice with Peptide 6, behavioral and immunohistochemical studies and data analysis, and wrote the manuscript. L. Wanka synthesized and purified the peptide 6. Y.-C. Tung and M. C. Cárdenas-Aguayo carried out the Western blot analysis for changes in level of tau and phospho-tau. F. M. LaFerla provided the breeding pairs of 3xTg-AD mice. K. Iqbal and I. Grundke-Iqbal conceived and directed all phases of the study, including the manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Blanchard, J., Wanka, L., Tung, YC. et al. Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Aβ and tau pathologies in 3xTg-AD mice. Acta Neuropathol 120, 605–621 (2010). https://doi.org/10.1007/s00401-010-0734-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-010-0734-6

Keywords

Navigation