Interferon-γ and Tumor Necrosis Factor-α Regulate Amyloid-β Plaque Deposition and β-Secretase Expression in Swedish Mutant APP Transgenic Mice

Yamamoto, Masaru; Kiyota, Tomomi; Horiba, Masahide; Buescher, James L.; Walsh, Shannon M.; Gendelman, Howard E.; Ikezu, Tsuneya

doi:10.2353/ajpath.2007.060378

Cited by 367Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

Interferon-γ and Tumor Necrosis Factor-α Regulate Amyloid-β Plaque Deposition and β-Secretase Expression in Swedish Mutant APP Transgenic Mice

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Yamamoto, Masaru, Kiyota, Tomomi, Horiba, Masahide, Buescher, James L., Walsh, Shannon M., Gendelman, Howard E., Ikezu, Tsuneya·2007·The American Journal of Pathology

DOI 10.2353/ajpath.2007.060378PMC PMC1851864

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Abstract

Reactive astrocytes and microglia in Alzheimer's disease surround amyloid plaques and secrete proinflammatory cytokines that affect neuronal function. Relationship between cytokine signaling and amyloid-beta peptide (Abeta) accumulation is poorly understood. Thus, we generated a novel Swedish beta-amyloid precursor protein mutant (APP) transgenic mouse in which the interferon (IFN)-gamma receptor type I was knocked out (APP/GRKO). IFN-gamma signaling loss in the APP/GRKO mice reduced gliosis and amyloid plaques at 14 months of age. Aggregated Abeta induced IFN-gamma production from co-culture of astrocytes and microglia, and IFN-gamma elicited tumor necrosis factor (TNF)-alpha secretion in wild type (WT) but not GRKO microglia co-cultured with astrocytes. Both IFN-gamma and TNF-alpha enhanced Abeta production from APP-expressing astrocytes and cortical neurons. TNF-alpha directly stimulated beta-site APP-cleaving enzyme (BACE1) expression and enhanced beta-processing of APP in astrocytes. The numbers of reactive astrocytes expressing BACE1 were increased in APP compared with APP/GRKO mice in both cortex and hippocampus. IFN-gamma and TNF-alpha activation of WT microglia suppressed Abeta degradation, whereas GRKO microglia had no changes. These results support the idea that glial IFN-gamma and TNF-alpha enhance Abeta deposition through BACE1 expression and suppression of Abeta clearance. Taken together, these observations suggest that proinflammatory cytokines are directly linked to Alzheimer's disease pathogenesis.

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Inflammatory proteins such as interleukin-1β, tumor necrosis factor-α, and interferon-γ can alter APP expression, APP processing, or Aβ transport.
“Because inflammatory proteins (e.g., interleukin-1β, tumor necrosis factor–α, and interferon-γ) can alter APP expression, APP processing, or Aβ transport (47–50), the inflammatory changes caused by the deletion of Abi3 locus may have contributed to the increase in APP protein level and subsequently Aβ accumulation.”
From Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [47]
The Results section, “TNF-α Enhances Astrocyte BACE1 Expression and Aβ Production” (page unavailable), reports that TNF-α increased β-processing of APP; the Discussion also links IFN-γ to increased Aβ production through TNF-α. The paper does not substantively discuss an effect of interleukin-1β outside its reference list, so it supports the claim’s general point about inflammatory proteins and APP processing, but not all three examples attributed to it. (LLM, conf=0.82)
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Autoantibodies against β‐amyloid are common in Alzheimer's disease and help control plaque burden
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Authors: Yamamoto, M., Kiyota, T., Horiba, M., Buescher, J. L., Walsh, S. M., Gendelman, H. E., & Ikezu, T.
Affiliations: Nebraska Medical Center (US)
University of Nebraska Medical Center (US)
Corresponding author: Ikezu, Tsuneya
ORCID: Kiyota, Tomomi
Walsh, Shannon M.
Gendelman, Howard E.
Ikezu, Tsuneya
Venue: The American Journal of Pathology
Publisher: Elsevier BV
Published: 2007-02
Volume: 170
Issue: 2
Pages: 680-692
ISSN: 0002-9440 (ISSN-L)
DOI: 10.2353/ajpath.2007.060378
PMC: PMC1851864
OpenAlex: W2062084653
Cited by: 367
References: 62
Citations by year: 2026: 6 · 2025: 14 · 2024: 16 · 2023: 16 · 2022: 19 · 2021: 26 · 2020: 21 · 2019: 19 · 2018: 23 · 2017: 18 · 2016: 18 · 2015: 16 · 2014: 25 · 2013: 22 · 2012: 20
FWCI: 14.54
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: American Journal Of Pathology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Fondation pour la Recherche sur Alzheimer
National Institutes of Health
National Institute of Neurological Disorders and Stroke (P01NS043985)
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: Alzheimer's disease, amyloid plaques, interferon-gamma, TNF-α, beta-secretase, BACE1, APP transgenic mice, astrocytes, microglia, gliosis, inflammatory cytokines, amyloid-beta clearance, amyloid beta degradation, APP processing
MeSH terms: Interferon gamma Receptor, Alzheimer Disease, Animals, Astrocytes, Cells, Cultured, Cerebellar Cortex, Enzyme Activation, Gliosis, Humans, Interferon-gamma, Neurons, Tumor Necrosis Factor-alpha, Signal Transduction, Gene Expression Regulation, Enzymologic, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Receptors, Interferon, Microglia, Mice, Knockout, Coculture Techniques, Mice, Amyloid Precursor Protein Secretases, Plaque, Amyloid

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Interferon-γ and Tumor Necrosis Factor-α Regulate Amyloid-β Plaque Deposition and β-Secretase Expression in Swedish Mutant APP Transgenic Mice

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