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CNS expression of anti‐inflammatory cytokine interleukin‐4 attenuates Alzheimer's disease‐like pathogenesis in APP+PS1 bigenic mice
Author(s) -
Kiyota Tomomi,
Okuyama Satoshi,
Swan Russell J.,
Jacobsen Michael T.,
Gendelman Howard E.,
Ikezu Tsuneya
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-155317
Subject(s) - medicine , gerontology , center (category theory) , chemistry , crystallography
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 antiinflammatory 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.—Kiyota, T., Okuyama, S., Swan, R. J., Jacobsen, M. T., Gendelman, H. E., Ikezu, T. CNS expression of anti‐inflammatory cytokine interleukin‐4 attenuates Alzheimer's disease‐like pathogenesis in APP+PS1 bigenic mice. FASEB J. FASEB J . 24, 3093–3102 (2010). www.fasebj.org