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Keywords:

  • ageing;
  • Alzheimer's disease;
  • interleukin-6;
  • macrophage-colony stimulating factor;
  • oxidative stress

Summary

β-Amyloid (Aβ) plaques are characteristic hallmarks of Alzheimer's disease (AD). In AD, it has been suggested that activation of microglial cells might be the link between Aβ deposition and neuronal degeneration. Activated microglia are associated with senile plaques and produce free radicals and inflammatory cytokines. However, it is still not clear whether Aβ needs a prestimulated environment to exert its proinflammatory potential. Advanced glycation endproducts (AGEs), protein-bound oxidation products of sugars, have been shown to accumulate in senile plaques and could induce a silent but chronic inflammation in the AD brain. We tested whether Aβ acts as an amplifier of a submaximal proinflammatory response initiated by exposure to chicken egg albumin-AGE, lipopolysaccharide or interferon-γ. Synthetic Aβ was used to produce three different samples (Aβ-fibrilar; Aβ-aggregated; Aβ-AGE), which were characterized for β-sheeted fibrils by the thioflavin-T test and electron microscopy. As markers of microglial activation, nitric oxide, interleukin-6, macrophage-colony stimulation factor and tumour necrosis factor-α production was measured. All three Aβ samples alone could not induce a detectable microglial response. The combination of Aβ preparations, however, with the coinducers provoked a strong microglial response, whereby Aβ-AGE and fibrilar Aβ were more potent inflammatory signals than aggregated Aβ. Thus, Aβ in senile plaques can amplify microglial activation by a coexisting submaximal inflammatory stimulus. Hence, anti-inflammatory therapeutics could either target the primary proinflammatory signal (e.g. by limiting AGE-formation by AGE inhibitors or cross-link breakers) or the amplifyer Aβ (e.g. by limiting Aβ production by β- or γ-secretase inhibitors).