Possible relationships between ischemia, amyloid-β, and neuroinflammation. Origlia and colleagues (2014) demonstrated that ischemia can induce amyloid-β synthesis, microglial RAGE-dependent JNK activation, p38MAPK activation, and IL-1β release that results in synaptic dysfunction. They suggest a feedforward loop whereby the presence of amyloid-β during ischemia exacerbates neuroinflammation, which promotes additional amyloid-β production. To close this loop, further work should investigate the contributions of microglial, astrocyte, neuronal, and endothelial RAGE, and neuroinflammation to amyloid-β overproduction during OGD. While the molecular events leading to IL-1β production required JNK and p38MAPK activation, the specific cell types expressing these activated kinases remain to be determined. Astrocytes and neurons, as well as microglia, activate JNK and p38MAPK after ischemia (Wu et al., 2000) and any of these cell types could be involved in a feedforward loop that supports IL-1β release from microglia and postischemic synaptic dysfunction. Interactions established in the study (solid lines) and interactions suggested in previous studies (dashed lines) that could support a feedforward mechanism are shown.