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

Loss of IFN-gamma signaling in APP/GRKO mice reduced gliosis and amyloid plaques at 14 months of age.

• Reactive astrocytes and microglia surrounding amyloid plaques secrete proinflammatory cytokines that may affect neuronal function.
• Aggregated amyloid-beta peptide (Abeta) can induce IFN-gamma production from co-cultured astrocytes and microglia.
• IFN-gamma stimulates tumor necrosis factor (TNF)-alpha secretion in wild type microglia but not in GRKO microglia.
• Both IFN-gamma and TNF-alpha may enhance Abeta production from astrocytes and cortical neurons expressing the amyloid precursor protein.
• TNF-alpha could directly stimulate the expression of an enzyme that cleaves the amyloid precursor protein, leading to increased Abeta production.
• Proinflammatory cytokines like IFN-gamma and TNF-alpha are associated with enhanced amyloid deposition and reduced clearance in Alzheimer's disease.

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