Crosstalk between RAGE and its ligands in Alzheimer’s disease. RAGE mediates A brain influx and accumulation. A directly or indirectly triggers dysregulation of calcium homeostasis thereby activating the S100 proteins. RAGE-mediated activation of glia cells results in the activation of NF-B driven gene transcription, and the release of inflammatory cytokines such as IL-1, IL-6, TNF-, IL-1, M-CSF and S100B. The brain of AD patients becomes the site of intense inflammation and oxidative stress that facilitates formation of AGEs. S100B, A and AGEs as well as other RAGE ligands including TTR, HMGB1, S100A6, S100A8/A9, and S100A12 accumulate in the brain during the course of the disease. Secreted S100B and chronic RAGE activation trigger several AD-associated neuropathological features including microglia activation, the production of reactive oxygen species (ROS), neurite degeneration, NFT formation, and neuronal apoptosis ultimately leading to memory impairment.
