Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice

Gene Therapy volume 19, pages 724–733 (2012)Cite this article

Abstract

Brain inflammation is a double-edged sword. It is required for brain repair in acute damage, whereas chronic inflammation and autoimmune disorders are neuropathogenic. Certain proinflammatory cytokines and chemokines are closely related to cognitive dysfunction and neurodegeneration. Representative anti-inflammatory cytokines, such as interleukin (IL)-10, can suppress neuroinflammation and have significant therapeutic potentials in ameliorating neurodegenerative disorders such as Alzheimer's disease (AD). Here, we show that adeno-associated virus (AAV) serotype 2/1 hybrid-mediated neuronal expression of the mouse IL-10 gene ameliorates cognitive dysfunction in amyloid precursor protein+ presenilin-1 bigenic mice. AAV2/1 infection of hippocampal neurons resulted in sustained expression of IL-10 without its leakage into the blood, reduced astro/microgliosis, enhanced plasma amyloid-β peptide (Aβ) levels and enhanced neurogenesis. Moreover, increased levels of IL-10 improved spatial learning, as determined by the radial arm water maze. Finally, IL-10-stimulated microglia enhanced proliferation but not differentiation of primary neural stem cells in the co-culture system, whereas IL-10 itself had no effect. Our data suggest that IL-10 gene delivery has a therapeutic potential for a non-Aβ-targeted treatment of AD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Laurence JA, Fatemi SH . Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum 2005; 4: 206–210.

    Article  CAS  Google Scholar 

  2. Skaper SD . The brain as a target for inflammatory processes and neuroprotective strategies. Ann N Y Acad Sci 2007; 1122: 23–34.

    Article  CAS  Google Scholar 

  3. McNally L, Bhagwagar Z, Hannestad J . Inflammation, glutamate, and glia in depression: a literature review. CNS Spectr 2008; 13: 501–510.

    Article  Google Scholar 

  4. van der Valk P, Amor S . Preactive lesions in multiple sclerosis. Curr Opin Neurol 2009; 22: 207–213.

    PubMed  Google Scholar 

  5. Farfara D, Lifshitz V, Frenkel D . Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease. J Cell Mol Med 2008; 12: 762–780.

    Article  CAS  Google Scholar 

  6. Streit WJ . Microglial response to brain injury: a brief synopsis. Toxicol Pathol 2000; 28: 28–30.

    Article  CAS  Google Scholar 

  7. Monje ML, Mizumatsu S, Fike JR, Palmer TD . Irradiation induces neural precursor-cell dysfunction. Nat Med 2002; 8: 955–962.

    Article  CAS  Google Scholar 

  8. Monje ML, Toda H, Palmer TD . Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003; 302: 1760–1765.

    Article  CAS  Google Scholar 

  9. van der Most PJ, Dolga AM, Nijholt IM, Luiten PG, Eisel UL . Statins: mechanisms of neuroprotection. Prog Neurobiol 2009; 88: 64–75.

    Article  CAS  Google Scholar 

  10. Ray B, Lahiri DK . Neuroinflammation in Alzheimer's disease: different molecular targets and potential therapeutic agents including curcumin. Curr Opin Pharmacol 2009; 9: 434–444.

    Article  CAS  Google Scholar 

  11. Birmingham K, Frantz S . Set back to Alzheimer vaccine studies. Nat Med 2002; 8: 199–200.

    Article  CAS  Google Scholar 

  12. Frenkel D, Maron R, Burt DS, Weiner HL . Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease. J Clin Invest 2005; 115: 2423–2433.

    Article  CAS  Google Scholar 

  13. Butovsky O, Koronyo-Hamaoui M, Kunis G, Ophir E, Landa G, Cohen H et al. Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci U S A 2006; 103: 11784–11789.

    Article  CAS  Google Scholar 

  14. Frenkel D, Puckett L, Petrovic S, Xia W, Chen G, Vega J et al. A nasal proteosome adjuvant activates microglia and prevents amyloid deposition. Ann Neurol 2008; 63: 591–601.

    Article  CAS  Google Scholar 

  15. Stern JN, Keskin DB, Zhang H, Lv H, Kato Z, Strominger JL . Amino acid copolymer-specific IL-10-secreting regulatory T cells that ameliorate autoimmune diseases in mice. Proc Natl Acad Sci U S A 2008; 105: 5172–5176.

    Article  CAS  Google Scholar 

  16. Howard M, O’Garra A, Ishida H, de Waal Malefyt R, de Vries J . Biological properties of interleukin 10. J Clin Immunol 1992; 12: 239–247.

    Article  CAS  Google Scholar 

  17. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A . Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19: 683–765.

    Article  CAS  Google Scholar 

  18. Lynch AM, Walsh C, Delaney A, Nolan Y, Campbell VA, Lynch MA . Lipopolysaccharide-induced increase in signalling in hippocampus is abrogated by IL-10–a role for IL-1 beta? J Neurochem 2004; 88: 635–646.

    Article  CAS  Google Scholar 

  19. Arimoto T, Choi DY, Lu X, Liu M, Nguyen XV, Zheng N et al. Interleukin-10 protects against inflammation-mediated degeneration of dopaminergic neurons in substantia nigra. Neurobiol Aging 2007; 28: 894–906.

    Article  CAS  Google Scholar 

  20. Qian L, Block ML, Wei SJ, Lin CF, Reece J, Pang H et al. Interleukin-10 protects lipopolysaccharide-induced neurotoxicity in primary midbrain cultures by inhibiting the function of NADPH oxidase. J Pharmacol Exp Ther 2006; 319: 44–52.

    Article  CAS  Google Scholar 

  21. Zhou Z, Peng X, Insolera R, Fink DJ, Mata M . IL-10 promotes neuronal survival following spinal cord injury. Exp Neurol 2009; 220: 183–190.

    Article  CAS  Google Scholar 

  22. Richwine AF, Sparkman NL, Dilger RN, Buchanan JB, Johnson RW . Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide. Brain Behav Immun 2009; 23: 794–802.

    Article  CAS  Google Scholar 

  23. Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J et al. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 2008; 14: 681–687.

    Article  CAS  Google Scholar 

  24. Xiao X, Li J, Samulski RJ . Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J Virol 1996; 70: 8098–8108.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Xiao X, Li J, McCown TJ, Samulski RJ . Gene transfer by adeno-associated virus vectors into the central nervous system. Exp Neurol 1997; 144: 113–124.

    Article  CAS  Google Scholar 

  26. Dudus L, Anand V, Acland GM, Chen SJ, Wilson JM, Fisher KJ et al. Persistent transgene product in retina, optic nerve and brain after intraocular injection of rAAV. Vision Res 1999; 39: 2545–2553.

    Article  CAS  Google Scholar 

  27. Guy J, Qi X, Muzyczka N, Hauswirth WW . Reporter expression persists 1 year after adeno-associated virus-mediated gene transfer to the optic nerve. Arch Ophthalmol 1999; 117: 929–937.

    Article  CAS  Google Scholar 

  28. Peel AL, Klein RL . Adeno-associated virus vectors: activity and applications in the CNS. J Neurosci Methods 2000; 98: 95–104.

    Article  CAS  Google Scholar 

  29. Passini MA, Watson DJ, Vite CH, Landsburg DJ, Feigenbaum AL, Wolfe JH . Intraventricular brain injection of adeno-associated virus type 1 (AAV1) in neonatal mice results in complementary patterns of neuronal transduction to AAV2 and total long-term correction of storage lesions in the brains of beta-glucuronidase-deficient mice. J Virol 2003; 77: 7034–7040.

    Article  CAS  Google Scholar 

  30. Kiyota T, Yamamoto M, Schroder B, Jacobsen MT, Swan RJ, Lambert MP et al. AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice. Mol Ther 2009; 17: 803–809.

    Article  CAS  Google Scholar 

  31. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996; 274: 99–102.

    Article  CAS  Google Scholar 

  32. Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J et al. Increased amyloid-beta42 in brains of mice expressing mutant presenilin 1. Nature 1996; 383: 710–713.

    Article  CAS  Google Scholar 

  33. Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998; 4: 97–100.

    Article  CAS  Google Scholar 

  34. Kiyota T, Okuyama S, Swan RJ, Jacobsen MT, Gendelman HE, Ikezu T . CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer's disease-like pathogenesis in APP+PS1 bigenic mice. FASEB J 2010; 24: 3093–3102.

    Article  CAS  Google Scholar 

  35. Tan J, Town T, Crawford F, Mori T, DelleDonne A, Crescentini R et al. Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nat Neurosci 2002; 5: 1288–1293.

    Article  CAS  Google Scholar 

  36. He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C et al. Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice. J Cell Biol 2007; 178: 829–841.

    Article  CAS  Google Scholar 

  37. Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE et al. Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol 2007; 170: 680–692.

    Article  CAS  Google Scholar 

  38. Aharoni R, Arnon R, Eilam R . Neurogenesis and neuroprotection induced by peripheral immunomodulatory treatment of experimental autoimmune encephalomyelitis. J Neurosci 2005; 25: 8217–8228.

    Article  CAS  Google Scholar 

  39. Aharoni R, Kayhan B, Eilam R, Sela M, Arnon R . Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proc Natl Acad Sci U S A 2003; 100: 14157–14162.

    Article  CAS  Google Scholar 

  40. Rao MS, Shetty AK . Efficacy of doublecortin as a marker to analyse the absolute number and dendritic growth of newly generated neurons in the adult dentate gyrus. Eur J Neurosci 2004; 19: 234–246.

    Article  Google Scholar 

  41. Zhang C, McNeil E, Dressler L, Siman R . Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer's disease. Exp Neurol 2007; 204: 77–87.

    Article  CAS  Google Scholar 

  42. Carpentier PA, Palmer TD . Immune influence on adult neural stem cell regulation and function. Neuron 2009; 64: 79–92.

    Article  CAS  Google Scholar 

  43. Plunkett JA, Yu CG, Easton JM, Bethea JR, Yezierski RP . Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat. Exp Neurol 2001; 168: 144–154.

    Article  CAS  Google Scholar 

  44. Dietrich WD, Busto R, Bethea JR . Postischemic hypothermia and IL-10 treatment provide long-lasting neuroprotection of CA1 hippocampus following transient global ischemia in rats. Exp Neurol 1999; 158: 444–450.

    Article  CAS  Google Scholar 

  45. Sloane E, Ledeboer A, Seibert W, Coats B, van Strien M, Maier SF et al. Anti-inflammatory cytokine gene therapy decreases sensory and motor dysfunction in experimental Multiple Sclerosis: MOG-EAE behavioral and anatomical symptom treatment with cytokine gene therapy. Brain Behav Immun 2009; 23: 92–100.

    Article  CAS  Google Scholar 

  46. Johnston LC, Su X, Maguire-Zeiss K, Horovitz K, Ankoudinova I, Guschin D et al. Human interleukin-10 gene transfer is protective in a rat model of Parkinson's disease. Mol Ther 2008; 16: 1392–1399.

    Article  CAS  Google Scholar 

  47. Abraham KE, McMillen D, Brewer KL . The effects of endogenous interleukin-10 on gray matter damage and the development of pain behaviors following excitotoxic spinal cord injury in the mouse. Neuroscience 2004; 124: 945–952.

    Article  CAS  Google Scholar 

  48. Jackson CA, Messinger J, Peduzzi JD, Ansardi DC, Morrow CD . Enhanced functional recovery from spinal cord injury following intrathecal or intramuscular administration of poliovirus replicons encoding IL-10. Virology 2005; 336: 173–183.

    Article  CAS  Google Scholar 

  49. Yamamoto M, Kiyota T, Walsh SM, Liu J, Kipnis J, Ikezu T . Cytokine-mediated inhibition of fibrillar amyloid-beta peptide degradation by human mononuclear phagocytes. J Immunol 2008; 181: 3877–3886.

    Article  CAS  Google Scholar 

  50. Kim J, Onstead L, Randle S, Price R, Smithson L, Zwizinski C et al. Abeta40 inhibits amyloid deposition in vivo. J Neurosci 2007; 27: 627–633.

    Article  CAS  Google Scholar 

  51. Wu B, Ueno M, Onodera M, Kusaka T, Huang CL, Hosomi N et al. RAGE, LDL receptor, and LRP1 expression in the brains of SAMP8. Neurosci Lett 2009; 461: 100–105.

    Article  CAS  Google Scholar 

  52. Bruel-Jungerman E, Rampon C, Laroche S . Adult hippocampal neurogenesis, synaptic plasticity and memory: facts and hypotheses. Rev Neurosci 2007; 18: 93–114.

    Article  CAS  Google Scholar 

  53. Lee E, Son H . Adult hippocampal neurogenesis and related neurotrophic factors. BMB Rep 2009; 42: 239–244.

    Article  CAS  Google Scholar 

  54. Cacci E, Ajmone-Cat MA, Anelli T, Biagioni S, Minghetti L . In vitro neuronal and glial differentiation from embryonic or adult neural precursor cells are differently affected by chronic or acute activation of microglia. Glia 2008; 56: 412–425.

    Article  Google Scholar 

  55. Levy Y, Brouet JC . Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein. J Clin Invest 1994; 93: 424–428.

    Article  CAS  Google Scholar 

  56. Itoh K, Hirohata S . The role of IL-10 in human B cell activation, proliferation, and differentiation. J Immunol 1995; 154: 4341–4350.

    CAS  PubMed  Google Scholar 

  57. Klein RL, Hamby ME, Sonntag CF, Millard WJ, King MA, Meyer EM . Measurements of vector-derived neurotrophic factor and green fluorescent protein levels in the brain. Methods 2002; 28: 286–292.

    Article  CAS  Google Scholar 

  58. West MJ . Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias. Trends Neurosci 1999; 22: 51–61.

    Article  CAS  Google Scholar 

  59. Xu J, Tsutsumi K, Tokuraku K, Estes KA, Hisanaga SI, Ikezu T . Actin interaction and regulation of cyclin-dependent kinase 5/p35 complex activity. J Neurochem 2011; 116:192–204.

    Article  CAS  Google Scholar 

  60. Kiyota T, Yamamoto M, Xiong H, Lambert MP, Klein WL, Gendelman HE et al. CCL2 accelerates microglia-mediated Abeta oligomer formation and progression of neurocognitive dysfunction. PLoS One 2009; 4: e6197.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Drs K Hsiao-Ashe for providing Tg2576 mice, K Duff for providing M146L PS1 mice, R Klein for pGFP plasmid, University of Pennsylvania Gene Therapy Program for recombinant AAV1 vectors and Megan Varnum for editing of the manuscript. This work is supported by the Vada Kinman Oldfield Alzheimer's Research Fund (TK and TI), UNMC Brain Bank Core Fund (TI), NIH P01 NS043985 (TI), R01 MH083523 (TI) and R21 AG032600 (TI).

Author information

Authors and Affiliations

  1. Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, USA

    T Kiyota, R J Swan, M T Jacobsen, S J Andrews & T Ikezu

  2. Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA

    T Kiyota, R J Swan, M T Jacobsen, S J Andrews & T Ikezu

  3. Departments of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA

    K L Ingraham & T Ikezu

  4. Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    T Ikezu

  5. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    T Ikezu

  6. Disease Center, Boston University School of Medicine, Boston, MA, USA

    T Ikezu

Authors
  1. T Kiyota
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K L Ingraham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R J Swan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M T Jacobsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S J Andrews
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Ikezu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Ikezu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Gene Therapy website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kiyota, T., Ingraham, K., Swan, R. et al. AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice. Gene Ther 19, 724–733 (2012). https://doi.org/10.1038/gt.2011.126

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2011.126

Keywords

This article is cited by

Search

Advanced search

Quick links