Beta-amyloid peptide potentiates inflammatory responses induced by lipopolysaccharide, interferon -gamma and 'advanced glycation endproducts' in a murine microglia cell line.

Abstract

beta-Amyloid (Abeta) 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 Abeta 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 Abeta 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 Abeta acts as an amplifier of a submaximal proinflammatory response initiated by exposure to chicken egg albumin-AGE, lipopolysaccharide or interferon-gamma. Synthetic Abeta was used to produce three different samples (Abeta-fibrilar; Abeta-aggregated; Abeta-AGE), which were characterized for beta-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-alpha production was measured. All three Abeta samples alone could not induce a detectable microglial response. The combination of Abeta preparations, however, with the coinducers provoked a strong microglial response, whereby Abeta-AGE and fibrilar Abeta were more potent inflammatory signals than aggregated Abeta. Thus, Abeta 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 Abeta (e.g. by limiting Abeta production by beta- or gamma-secretase inhibitors).