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An experimental rat model of sporadic Alzheimer’s disease and rescue of cognitive impairment with a neurotrophic peptide

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Abstract

Alzheimer’s disease (AD) is multifactorial and, to date, no single cause of the sporadic form of this disease, which accounts for over 99% of the cases, has been established. In AD brain, protein phosphatase-2A (PP2A) activity is known to be compromised due to the cleavage and translocation of its potent endogenous inhibitor, I PP2A2 , from the neuronal nucleus to the cytoplasm. Here, we show that adeno-associated virus vector-induced expression of the N-terminal I2NTF and C-terminal I2CTF halves of I PP2A2 , also called SET, in brain reproduced key features of AD in Wistar rats. The I2NTF–CTF rats showed a decrease in brain PP2A activity, abnormal hyperphosphorylation and aggregation of tau, a loss of neuronal plasticity and impairment in spatial reference and working memories. To test whether early pharmacologic intervention with a neurotrophic molecule could rescue neurodegeneration and behavioral deficits, 2.5-month-old I2NTF–CTF rats and control littermates were treated for 40 days with Peptide 6, an 11-mer peptide corresponding to an active region of the ciliary neurotrophic factor. Peripheral administration of Peptide 6 rescued neurodegeneration and cognitive deficit in I2NTF–CTF animals by increasing dentate gyrus neurogenesis and mRNA level of brain derived neurotrophic factor. Moreover, Peptide 6-treated I2NTF–CTF rats showed a significant increase in dendritic and synaptic density as reflected by increased expression of synapsin I, synaptophysin and MAP2, especially in the pyramidal neurons of CA1 and CA3 of the hippocampus.

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References

  1. Arendt T (2009) Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol 118:167–179

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Blanchard J, Chohan MO, Li B, Liu F, Iqbal K, Grundke-Iqbal I (2010) Beneficial effect of a CNTF tetrapeptide on adult hippocampal neurogenesis, neuronal plasticity, and spatial memory in mice. J Alzheimers Dis 21:1185–1195

    PubMed  CAS  Google Scholar 

  4. Blanchard J, Wanka L, Tung YC et al (2010) Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Abeta and tau pathologies in 3xTg-AD mice. Acta Neuropathol 120:605–621

    Article  PubMed  CAS  Google Scholar 

  5. Chohan MO, Li B, Blanchard J et al (2011) Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide. Neurobiol Aging 32:1420–1434

    Article  PubMed  CAS  Google Scholar 

  6. de Barreda EG, Avila J (2010) Is tau a suitable therapeutical target in tauopathies? World J Biol Chem 1:81–84

    Article  PubMed  Google Scholar 

  7. Deng W, Aimone JB, Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 11:339–350

    Article  PubMed  CAS  Google Scholar 

  8. Garcia P, Youssef I, Utvik JK 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  PubMed  CAS  Google Scholar 

  9. Ge S, Yang CH, Hsu KS, Ming GL, Song H (2007) A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 54:559–566

    Article  PubMed  CAS  Google Scholar 

  10. 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  PubMed  CAS  Google Scholar 

  11. Golde TE, Schneider LS, Koo EH (2011) Anti-abeta therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron 69:203–213

    Article  PubMed  CAS  Google Scholar 

  12. Gong CX, Lidsky T, Wegiel J, Zuck L, Grundke-Iqbal I, Iqbal K (2000) Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer’s disease. J Biol Chem 275:5535–5544

    Article  PubMed  CAS  Google Scholar 

  13. Gong CX, Singh TJ, Grundke-Iqbal I, Iqbal K (1993) Phosphoprotein phosphatase activities in Alzheimer disease brain. J Neurochem 61:921–927

    Article  PubMed  CAS  Google Scholar 

  14. Greenberg SG, Davies P (1990) A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc Natl Acad Sci USA 87:5827–5831

    Article  PubMed  CAS  Google Scholar 

  15. 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  PubMed  CAS  Google Scholar 

  16. Grundke-Iqbal I, Vorbrodt AW, Iqbal K, Tung YC, Wang GP, Wisniewski HM (1988) Microtubule-associated polypeptides tau are altered in Alzheimer paired helical filaments. Brain Res 464:43–52

    PubMed  CAS  Google Scholar 

  17. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  PubMed  CAS  Google Scholar 

  18. Hasegawa M, Watanabe A, Takio K et al (1993) Characterization of two distinct monoclonal antibodies to paired helical filaments: further evidence for fetal-type phosphorylation of the tau in paired helical filaments. J Neurochem 60:2068–2077

    Article  PubMed  CAS  Google Scholar 

  19. Hefti F (1994) Growth factors and neurodegeneration. In: Calne DB (ed) Neurodegenerative diseases. W.B. Saunders Company, Philadelphia, pp 177–194

  20. Henckaerts E, Dutheil N, Zeltner N et al (2009) Site-specific integration of adeno-associated virus involves partial duplication of the target locus. Proc Natl Acad Sci USA 106:7571–7576

    Article  PubMed  CAS  Google Scholar 

  21. Hitoshi S, Seaberg RM, Koscik C et al (2004) Primitive neural stem cells from the mammalian epiblast differentiate to definitive neural stem cells under the control of Notch signaling. Genes Dev 18:1806–1811

    Article  PubMed  CAS  Google Scholar 

  22. Hock C, Heese K, Hulette C, Rosenberg C, Otten U (2000) Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol 57:846–851

    Article  PubMed  CAS  Google Scholar 

  23. Holzer M, Bruckner MK, Beck M, Bigl V, Arendt T (2000) Modulation of APP processing and secretion by okadaic acid in primary guinea pig neurons. J Neural Transm 107:451–461

    Article  PubMed  CAS  Google Scholar 

  24. Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72:609–642

    Article  PubMed  CAS  Google Scholar 

  25. Iqbal K, Grundke-Iqbal I (2008) Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics, and prevention. J. Cell. Mol. Med. 12:38–55

    Article  PubMed  CAS  Google Scholar 

  26. Iqbal K, Grundke-Iqbal I (2011) Opportunities and challenges in developing Alzheimer disease therapeutics. Acta Neuropathol 122:543–549

    Google Scholar 

  27. 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  PubMed  CAS  Google Scholar 

  28. Kopke E, Tung YC, Shaikh S, Alonso AC, Iqbal K, Grundke-Iqbal I (1993) Microtubule-associated protein tau abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem 268:24374–24384

    PubMed  CAS  Google Scholar 

  29. Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T (1995) Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci USA 92:8856–8860

    Article  PubMed  CAS  Google Scholar 

  30. Lawlor PA, Bland RJ, Das P et al (2007) Novel rat Alzheimer’s disease models based on AAV-mediated gene transfer to selectively increase hippocampal Abeta levels. Mol Neurodegener 2:11

    Article  PubMed  Google Scholar 

  31. Li B, Yamamori H, Tatebayashi Y et al (2008) Failure of neuronal maturation in Alzheimer disease dentate gyrus. J Neuropathol Exp Neurol 67:78–84

    Article  PubMed  CAS  Google Scholar 

  32. Li M, Guo H, Damuni Z (1995) Purification and characterization of two potent heat-stable protein inhibitors of protein phosphatase 2A from bovine kidney. Biochemistry 34:1988–1996

    Article  PubMed  CAS  Google Scholar 

  33. Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2005) Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci 22:1942–1950

    Article  PubMed  Google Scholar 

  34. Liu R, Wang JZ (2009) Protein phosphatase 2A in Alzheimer’s disease. Pathophysiology 16:273–277

    Article  PubMed  Google Scholar 

  35. Lu B (2003) BDNF and activity-dependent synaptic modulation. Learn Mem 10:86–98

    Article  PubMed  Google Scholar 

  36. Madeira A, Pommet JM, Prochiantz A, Allinquant B (2005) SET protein (TAF1beta, I2PP2A) is involved in neuronal apoptosis induced by an amyloid precursor protein cytoplasmic subdomain. FASEB J 19:1905–1907

    PubMed  CAS  Google Scholar 

  37. Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44:5–21

    Article  PubMed  CAS  Google Scholar 

  38. Massa F, Koehl M, Wiesner T et al (2011) Conditional reduction of adult neurogenesis impairs bidirectional hippocampal synaptic plasticity. Proc Natl Acad Sci USA 108:6644–6649

    Article  PubMed  CAS  Google Scholar 

  39. Minichiello L, Korte M, Wolfer D et al (1999) Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24:401–414

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  41. Musumeci G, Sciarretta C, Rodriguez-Moreno A et al (2009) TrkB modulates fear learning and amygdalar synaptic plasticity by specific docking sites. J Neurosci 29:10131–10143

    Article  PubMed  CAS  Google Scholar 

  42. Naslund J, Haroutunian V, Mohs R et al (2000) Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283:1571–1577

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  44. Oddo S, Vasilevko V, Caccamo A, Kitazawa M, Cribbs DH, LaFerla FM (2006) Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles. J Biol Chem 281:39413–39423

    Article  PubMed  CAS  Google Scholar 

  45. Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW (1991) BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron 7:695–702

    Article  PubMed  CAS  Google Scholar 

  46. Qu D, Li Q, Lim HY et al (2002) The protein SET binds the neuronal Cdk5 activator p35nck5a and modulates Cdk5/p35nck5a activity. J Biol Chem 277:7324–7332

    Article  PubMed  CAS  Google Scholar 

  47. Rockenstein E, Adame A, Mante M, Moessler H, Windisch M, Masliah E (2003) The neuroprotective effects of Cerebrolysin in a transgenic model of Alzheimer’s disease are associated with improved behavioral performance. J Neural Transm 110:1313–1327

    Article  PubMed  CAS  Google Scholar 

  48. Sairanen M, Lucas G, Ernfors P, Castren M, Castren E (2005) Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 25:1089–1094

    Article  PubMed  CAS  Google Scholar 

  49. Seabrook GR, Ray WJ, Shearman M, Hutton M (2007) Beyond amyloid: the next generation of Alzheimer’s disease therapeutics. Mol Interv 7:261–270

    Article  PubMed  CAS  Google Scholar 

  50. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791

    Article  PubMed  CAS  Google Scholar 

  51. Seo SB, McNamara P, Heo S, Turner A, Lane WS, Chakravarti D (2001) Regulation of histone acetylation and transcription by INHAT, a human cellular complex containing the set oncoprotein. Cell 104:119–130

    Article  PubMed  CAS  Google Scholar 

  52. Sontag E, Luangpirom A, Hladik C et al (2004) Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology. J Neuropathol Exp Neurol 63:287–301

    PubMed  CAS  Google Scholar 

  53. Steiner B, Wolf S, Kempermann G (2006) Adult neurogenesis and neurodegenerative disease. Regen Med 1:15–28

    Article  PubMed  CAS  Google Scholar 

  54. Stern Y, Albert S, Tang MX, Tsai WY (1999) Rate of memory decline in AD is related to education and occupation: cognitive reserve? Neurology 53:1942–1947

    PubMed  CAS  Google Scholar 

  55. 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  PubMed  CAS  Google Scholar 

  56. Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, Kasai H (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319:1683–1687

    Article  PubMed  CAS  Google Scholar 

  57. Tanaka T, Zhong J, Iqbal K, Trenkner E, Grundke-Iqbal I (1998) The regulation of phosphorylation of tau in SY5Y neuroblastoma cells: the role of protein phosphatases. FEBS Lett 426:248–254

    Article  PubMed  CAS  Google Scholar 

  58. Tanimukai H, Grundke-Iqbal I, Iqbal K (2005) Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer’s disease. Am J Pathol 166:1761–1771

    Article  PubMed  CAS  Google Scholar 

  59. Tatebayashi Y, Lee MH, Li L, Iqbal K, Grundke-Iqbal I (2003) The dentate gyrus neurogenesis: a therapeutic target for Alzheimer’s disease. Acta Neuropathol (Berl) 105:225–232

    CAS  Google Scholar 

  60. Terry RD, Masliah E, Salmon DP 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  PubMed  CAS  Google Scholar 

  61. Tsujio I, Zaidi T, Xu J, Kotula L, Grundke-Iqbal I, Iqbal K (2005) Inhibitors of protein phosphatase-2A from human brain: structures, immunocytological localization and activities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau. FEBS Lett 579:363–372

    Article  PubMed  CAS  Google Scholar 

  62. Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2002) From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9:224–237

    Article  PubMed  Google Scholar 

  63. Vogelsberg-Ragaglia V, Schuck T, Trojanowski JQ, Lee VM (2001) PP2A mRNA expression is quantitatively decreased in Alzheimer’s disease hippocampus. Exp Neurol 168:402–412

    Article  PubMed  CAS  Google Scholar 

  64. Voronkov M, Braithwaite SP, Stock JB (2011) Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer’s disease. Future Med Chem 3:821–833

    Article  PubMed  CAS  Google Scholar 

  65. Wang JZ, Grundke-Iqbal I, Iqbal K (2007) Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25:59–68

    Article  PubMed  Google Scholar 

  66. Wang X, Blanchard J, Kohlbrenner E et al (2010) The carboxy-terminal fragment of inhibitor-2 of protein phosphatase-2A induces Alzheimer disease pathology and cognitive impairment. FASEB Journal 24:4420–4432

    Article  PubMed  CAS  Google Scholar 

  67. 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  PubMed  CAS  Google Scholar 

  68. Winton MJ, Lee EB, Sun E et al (2011) Intraneuronal APP, not free Abeta peptides in 3xTg-AD mice: implications for tau versus Abeta-mediated Alzheimer neurodegeneration. J Neurosci 31:7691–7699

    Article  PubMed  CAS  Google Scholar 

  69. Xu B, Gottschalk W, Chow A et al (2000) The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J Neurosci 20:6888–6897

    PubMed  CAS  Google Scholar 

  70. Yamada K, Mizuno M, Nabeshima T (2002) Role for brain-derived neurotrophic factor in learning and memory. Life Sci 70:735–744

    Article  PubMed  CAS  Google Scholar 

  71. Yang P, Arnold SA, Habas A, Hetman M, Hagg T (2008) Ciliary neurotrophic factor mediates dopamine D2 receptor-induced CNS neurogenesis in adult mice. J Neurosci 28:2231–2241

    Article  PubMed  CAS  Google Scholar 

  72. Yoshiyama Y, Higuchi M, Zhang B et al (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351

    Article  PubMed  CAS  Google Scholar 

  73. Zhang X, Poo MM (2002) Localized synaptic potentiation by BDNF requires local protein synthesis in the developing axon. Neuron 36:675–688

    Article  PubMed  CAS  Google Scholar 

  74. Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660

    Article  PubMed  CAS  Google Scholar 

  75. Zilka N, Filipcik P, Koson P et al (2006) Truncated tau from sporadic Alzheimer’s disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett 580:3582–3588

    Article  PubMed  CAS  Google Scholar 

  76. Zolotukhin S, Potter M, Zolotukhin I et al (2002) Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. Methods 28:158–167

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are most grateful to Dr. Aurelian Radu for his help in the design of the AAV1-I2NTF–CTF constructs, Dr. George Merz for his help in confocal microscopy, Drs. Ezzat El-Akkad and Jianhua Shi for their help in the preparation of the figures, and Ms. Janet Murphy for secretarial assistance. Studies described in this paper were supported in part by the New York State Office of People with Developmental Disabilities, NIH/NIA grant AG019158, and a research grant from EVER NeuroPharma, Unterach, Austria.

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  1. Xiaochuan Wang

    Present address: Pathophysiology Department, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Authors and Affiliations

  1. Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA

    Silvia Bolognin, Julie Blanchard, Xiaochuan Wang, Gustavo Basurto-Islas, Yunn Chyn Tung, Inge Grundke-Iqbal & Khalid Iqbal

  2. Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY, USA

    Erik Kohlbrenner

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  1. Silvia Bolognin
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Correspondence to Khalid Iqbal.

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Bolognin, S., Blanchard, J., Wang, X. et al. An experimental rat model of sporadic Alzheimer’s disease and rescue of cognitive impairment with a neurotrophic peptide. Acta Neuropathol 123, 133–151 (2012). https://doi.org/10.1007/s00401-011-0908-x

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