Neuroinflammation and Copper in Alzheimer’s Disease

Figure 1

Inflammatory processes in AD. (1) Sequential cleavage of APP by secretase proteins generates extracellular Aβ monomers, which aggregate to form toxic oligomers and plaques, a process accelerated by Cu and Zn ions. (2) Aβ oligomers may directly interact with immune components on astrocytes, potentially through TLR2/4 recognition, resulting in astrocyte-derived secretion of toxic proinflammatory mediators that act on neurons. (3) Microglia surrounding Aβ plaques may be polarised to the neurotoxic M1 phenotype through Aβ- or ROS-dependent inflammasome and TLR activation. (4) Microglia may also exert protective functions through intracellular Cu sequestration, direct phagocytic activity on plaques, and secretion on neuroprotective M2 mediators including IL-10. (5) The brain levels of Aβ are also controlled by RAGE- and LRP-1 mediated transport between the plasma and brain. Increased vascular RAGE in AD contributes to impaired clearance of Aβ from the CNS.