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 E.; Ikezu, Tsuneya

doi:10.1096/fj.10-155317

Cited by 212Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

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

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Kiyota, Tomomi, Okuyama, Satoshi, Swan, Russell J., Jacobsen, Michael T., Gendelman, Howard E., Ikezu, Tsuneya·2010·The FASEB Journal

DOI 10.1096/fj.10-155317PMC PMC2909296

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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 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

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IL4R is highly expressed in microglia and its ligand, the anti-inflammatory cytokine interleukin-4, attenuates AD symptoms in transgenic mice.
“Similar to the eotaxin-1 receptor, IL4R is also highly expressed in microglia14 and its ligand, the anti-inflammatory cytokine interleukin-4, attenuates AD symptoms in transgenic mice.46”
From Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease (2015) · cites this paper as [46]
Other studies have suggested that inhibition of inflammation attenuates amyloid-β pathology.
“However, other studies have suggested that inhibition of inflammation attenuates amyloid-β pathology35–37.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [36]
Anti-inflammatory processes mediated by IL-4 provide benefits in models representing early stages of neurodegenerative conditions such as AD and amyotrophic lateral sclerosis.
“Anti-inflammatory processes are associated with tissue repair, such as those mediated by IL-4, working through microglia and macrophages, and have been shown to provide benefits in models representing the early stages of neurodegenerative conditions, such as AD and amyotrophic lateral sclerosis, and other disorders related to cell death (45,72,73).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [73]

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Authors: Kiyota, T., Okuyama, S., Swan, R. J., Jacobsen, M. T., Gendelman, H. E., & Ikezu, T.
Affiliations: University of Nebraska Medical Center (US)
Corresponding author: Ikezu, Tsuneya
ORCID: Kiyota, Tomomi
Okuyama, Satoshi
Gendelman, Howard E.
Ikezu, Tsuneya
Venue: The FASEB Journal
Publisher: Wiley
Published: 2010-04-06
Volume: 24
Issue: 8
Pages: 3093-3102
ISSN: 0892-6638 (ISSN-L)
1530-6860
DOI: 10.1096/fj.10-155317
PMC: PMC2909296
OpenAlex: W2151409678
Cited by: 212
References: 66
Citations by year: 2026: 7 · 2025: 6 · 2024: 9 · 2023: 21 · 2022: 13 · 2021: 13 · 2020: 14 · 2019: 13 · 2018: 18 · 2017: 15 · 2016: 21 · 2015: 17 · 2014: 9 · 2013: 10 · 2012: 15
FWCI: 7.80
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: The FASEB Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Alzheimer's Research Foundation
University of Nebraska Medical Center
National Institutes of Health (P01 NS043985, R01 MH083523, R21 AG032600)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: IL-4, Alzheimer's disease, APP/PS1 mice, AAV gene delivery, hippocampus, anti-inflammatory cytokines, amyloid-beta oligomerization, amyloid-beta deposition, neurogenesis, NMDA receptor phosphorylation, spatial learning, glatiramer acetate, cytokine signaling
MeSH terms: Alzheimer Disease, Animals, Anti-Inflammatory Agents, Central Nervous System, Hippocampus, Mice, Mutant Strains, Neurons, Transfection, Genetic Therapy, Signal Transduction, Interleukin-4, Amyloid beta-Protein Precursor, Mice, Presenilin-1

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

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