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

Gene Ther. 2012 Jul;19(7):724-33. doi: 10.1038/gt.2011.126. Epub 2011 Sep 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / therapy*
  • Amyloid beta-Protein Precursor / blood
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Coculture Techniques
  • Cognition*
  • Dependovirus / genetics
  • Genetic Therapy / methods*
  • Hippocampus / metabolism
  • Interleukin-10 / genetics*
  • Maze Learning / physiology
  • Mice
  • Mice, Transgenic
  • Mutation
  • Neural Stem Cells
  • Neurogenesis / genetics*
  • Neurons / metabolism
  • Presenilin-1 / genetics*

Substances

  • Amyloid beta-Protein Precursor
  • Presenilin-1
  • Interleukin-10