Interferon-γ and tumor necrosis factor-α regulate amyloid-β plaque deposition and β-secretase expression in Swedish mutant APP transgenic mice

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

Research output: Contribution to journalArticle

234 Citations (Scopus)

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

Original languageEnglish (US)
Pages (from-to)680-692
Number of pages13
JournalAmerican Journal of Pathology
Volume170
Issue number2
DOIs
StatePublished - Feb 2007

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Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Amyloid Plaques
Mutant Proteins
Amyloid
Interferons
Transgenic Mice
Tumor Necrosis Factor-alpha
Astrocytes
Microglia
Cytokines
Alzheimer Disease
Interferon alpha-beta Receptor
Serum Amyloid A Protein
Gliosis
Coculture Techniques
Neuroglia
Hippocampus
Neurons
Enzymes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

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 Eliot; Ikezu, Tsuneya.

In: American Journal of Pathology, Vol. 170, No. 2, 02.2007, p. 680-692.

Research output: Contribution to journalArticle

Yamamoto, Masaru ; Kiyota, Tomomi ; Horiba, Masahide ; Buescher, James L. ; Walsh, Shannon M. ; Gendelman, Howard Eliot ; Ikezu, Tsuneya. / Interferon-γ and tumor necrosis factor-α regulate amyloid-β plaque deposition and β-secretase expression in Swedish mutant APP transgenic mice. In: American Journal of Pathology. 2007 ; Vol. 170, No. 2. pp. 680-692.
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