CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer's disease-like pathogenesis in APP+PS1 bigenic mice

Tomomi Kiyota, Satoshi Okuyama, Russell J. Swan, Michael T. Jacobsen, Howard Eliot Gendelman, Tsuneya Ikezu

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

Cytokines play an emerging role as neurotransmitters, neuromodulators, and neurohormones in the brain. This paradigm shift in cytokine function offers a new framework to understand their roles in ameliorating neurodegenerative disorders, such as Alzheimer's disease (AD). Molecular adjuvant therapy of AD animal models with glatiramer acetate induces anti-inflammatory responses and therapeutic effects. Although these effects are potentially mediated through anti-inflammatory cytokine signaling, the exact molecular identities and pathways are poorly understood. Here, we show that virus-mediated expression of the mouse interleukin (IL)-4 gene in β-amyloid precursor protein + presenilin-1 (APP+PS1) bigenic mice attenuates AD pathogenesis. Introduction of an adeno-associated viral (AAV) vector encoding IL-4 into the hippocampus resulted in sustained expression of IL-4, reduced astro/microgliosis, amyloid-β peptide (Aβ) oligomerization and deposition, and enhanced neurogenesis. Moreover, increased levels of IL-4 improved spatial learning, promoted phosphorylation of N-methyl-D-aspartate receptor subunit 2B at Tyr 1472, and enhanced its cell surface retention both in vivo and in vitro. Our data suggest that neuronal anti-inflammatory cytokine signaling may be a potential alternative target for non-Aβ-mediated treatment of AD.

Original languageEnglish (US)
Pages (from-to)3093-3102
Number of pages10
JournalFASEB Journal
Volume24
Issue number8
DOIs
StatePublished - Aug 1 2010

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Amyloid beta-Protein Precursor
Interleukin-4
Alzheimer Disease
Anti-Inflammatory Agents
Cytokines
Neurotransmitter Agents
Oligomerization
Phosphorylation
Neurogenesis
Therapeutic Uses
N-Methyl-D-Aspartate Receptors
Viruses
Amyloid
Neurodegenerative Diseases
Hippocampus
Brain
Animals
Animal Models
Genes
mouse presenilin 1

Keywords

  • AAV therapy
  • IL-4
  • Memory formation
  • NMDA receptor
  • Neurogenesis

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer's disease-like pathogenesis in APP+PS1 bigenic mice. / Kiyota, Tomomi; Okuyama, Satoshi; Swan, Russell J.; Jacobsen, Michael T.; Gendelman, Howard Eliot; Ikezu, Tsuneya.

In: FASEB Journal, Vol. 24, No. 8, 01.08.2010, p. 3093-3102.

Research output: Contribution to journalArticle

Kiyota, Tomomi ; Okuyama, Satoshi ; Swan, Russell J. ; Jacobsen, Michael T. ; Gendelman, Howard Eliot ; Ikezu, Tsuneya. / CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer's disease-like pathogenesis in APP+PS1 bigenic mice. In: FASEB Journal. 2010 ; Vol. 24, No. 8. pp. 3093-3102.
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