AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APPPS1 mice

T. Kiyota, K. L. Ingraham, R. J. Swan, M. T. Jacobsen, S. J. Andrews, T. Ikezu

Research output: Contribution to journalArticle

102 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)724-733
Number of pages10
JournalGene Therapy
Volume19
Issue number7
DOIs
StatePublished - Jul 1 2012

Fingerprint

Dependovirus
Neurogenesis
Interleukin-10
Cognition
Anti-Inflammatory Agents
Genes
Alzheimer Disease
Cytokines
Neural Stem Cells
Amyloid beta-Protein Precursor
Microglia
Encephalitis
Coculture Techniques
Serogroup
Chemokines
Amyloid
Neurodegenerative Diseases
Inflammation
Neurons
Water

Keywords

  • AAV
  • Alzheimer's disease
  • cytokines
  • neurogenesis
  • neuroimmunology
  • β-amyloid

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APPPS1 mice. / Kiyota, T.; Ingraham, K. L.; Swan, R. J.; Jacobsen, M. T.; Andrews, S. J.; Ikezu, T.

In: Gene Therapy, Vol. 19, No. 7, 01.07.2012, p. 724-733.

Research output: Contribution to journalArticle

Kiyota, T. ; Ingraham, K. L. ; Swan, R. J. ; Jacobsen, M. T. ; Andrews, S. J. ; Ikezu, T. / AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APPPS1 mice. In: Gene Therapy. 2012 ; Vol. 19, No. 7. pp. 724-733.
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