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Cited by 56Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and Treatments

Neutralization of granulocyte macrophage colony-stimulating factor decreases amyloid beta 1-42 and suppresses microglial activity in a transgenic mouse model of Alzheimer's disease

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Manczak, Maria, Mao, Peizhong, Nakamura, Kazuhiro, Bebbington, Christopher, Park, Byung, Reddy, P. Hemachandra·2009·Human Molecular Genetics
DOI 10.1093/hmg/ddp331PMC PMC2748895
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Abstract

The purpose of our study was to investigate microglia and astrocytes that are associated with human mutant amyloid precursor protein and amyloid beta (Abeta). We investigated whether the anti-granulocyte-macrophage-colony stimulating factor (GM-CSF) antibody can suppress microglial activity and decrease Abeta production in Alzheimer's disease transgenic mice (Tg2576 line). An antibody to mouse GM-CSF was introduced by intracerebroventricular (ICV) injections into the brains of 10-month-old Tg2576 male mice. We assessed the effect of several GM-CSF-associated cytokines on microglial activities and their association with Abeta using quantitative real-time RT-PCR, immunoblotting, immunohistochemistry analyses in anti-GM-CSF antibody-injected Tg2576 mice. Using sandwich ELISA technique, we measured intraneuronal Abeta in Tg2576 mice injected with GM-CSF antibody and PBS vehicle-injected control Tg2576 mice. Using double-labeling immunofluorescence analysis of intraneuronal Abeta, Abeta deposits and pro-inflammatory cytokines, we assessed the relationship between Abeta deposits and microglial markers in the Tg2576 mice, and also in the anti-GM-CSF antibody-injected Tg2576 mice. Our real-time RT-PCR analysis showed an increase in the mRNA expression of IL6, CD11c, IL1beta, CD40 and CD11b in the cerebral cortices of the Tg2576 mice compared with their littermate non-transgenic controls. Immunohistochemistry findings of microglial markers agreed with our real-time RT-PCR results. Interestingly, we found significantly decreased levels of activated microglia and Abeta deposits in anti-GM-CSF antibody-injected Tg2576 mice compared with PBS vehicle-injected Tg2576 mice. Findings from our real-time RT-PCR and immunoblotting analysis agreed with immunohistochemistry results. Our double-labeling analyses of intraneuronal Abeta and CD40 revealed that intraneuronal Abeta is associated with neuronal expression of CD40 in Tg2576 mice. Our quantitative sandwich ELISA analysis revealed decreased levels of soluble Abeta1-42 and increased levels of Abeta1-40 in Tg2576 mice injected with the anti-GM-CSF antibody, suggesting that anti-GM-CSF antibody alone decreases soluble Abeta1-42 production and suppresses microglial activity in Tg2576 mice. These findings indicating the ability of the anti-GM-CSF antibody to reduce Abeta1-42 and microglial activity in Tg2576 mice may have therapeutic implications for Alzheimer's disease.

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Cited by

Sorted by citations

Authors
Manczak, M., Mao, P., Nakamura, K., Bebbington, C., Park, B., & Reddy, P. H.
Affiliations
  • Oregon National Primate Research Center (US)
  • Oregon Health & Science University (US)
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2009-07-19
Volume
18
Issue
20
Pages
3876-3893
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddp331
PMC
PMC2748895
OpenAlex
W2120901401
Cited by
56
References
10
Citations by year
2026: 1 · 2025: 3 · 2024: 3 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 2 · 2017: 5 · 2016: 6 · 2014: 3 · 2013: 8 · 2012: 6
FWCI
2.88
Type
journal article
Language
en
Open access
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Oregon Health and Science University
  • National Institutes of Health (RR 00163, AG028072)
  • National Institute on Aging (AG026051, R03AG026051, R01AG028072, AG028072)
  • National Center for Research Resources (RR-00163.)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, amyloid-beta 42, Aβ40, GM-CSF, GM-CSF autoantibodies, microglial activation, Tg2576 mice, intraneuronal amyloid-beta, CD40, inflammatory cytokines, interleukin-6, IL-1β, CD11c, CD11b
MeSH terms
Alzheimer Disease, Animals, Antibodies, Astrocytes, Brain, Disease Models, Animal, Humans, Male, Mice, Transgenic, Peptide Fragments, Granulocyte-Macrophage Colony-Stimulating Factor, Cytokines, Amyloid beta-Peptides, Microglia, Mice

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