Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice

Am J Pathol. 2007 Feb;170(2):680-92. doi: 10.2353/ajpath.2007.060378.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / biosynthesis*
  • Amyloid beta-Peptides / biosynthesis*
  • Amyloid beta-Peptides / genetics
  • Animals
  • Aspartic Acid Endopeptidases / biosynthesis*
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Cells, Cultured
  • Cerebellar Cortex / metabolism
  • Cerebellar Cortex / pathology
  • Coculture Techniques
  • Enzyme Activation
  • Gene Expression Regulation, Enzymologic
  • Gliosis / genetics
  • Gliosis / metabolism
  • Gliosis / pathology
  • Humans
  • Interferon-gamma / metabolism*
  • Mice
  • Mice, Knockout
  • Microglia / metabolism
  • Microglia / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Plaque, Amyloid / metabolism*
  • Plaque, Amyloid / pathology
  • Receptors, Interferon / deficiency
  • Receptors, Interferon / metabolism
  • Signal Transduction / genetics
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Amyloid beta-Peptides
  • Receptors, Interferon
  • Tumor Necrosis Factor-alpha
  • interferon gamma receptor
  • Interferon-gamma
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse