Neuroinflammation and Copper in Alzheimer’s Disease

Figure 2

Hypothesised roles of copper in the inflammatory process of AD. (1) Clockwise from center. Cu and Zn induce the aggregation of Aβ in AD, leading to reduced neuronal intracellular bioavailable Cu. This may account for the reported reduced expression of the Cu-requiring proteins SOD1 and ATOX1 in AD. (2) Cp, the Cu-transport protein, which is elevated in AD, can promote Fe oxidation, inflammation [28], and increased extracellular Cu levels in the CNS. (3) Copper has been shown to potentiate the effects of cholesterol on inflammation-induced Aβ neurotoxicity through increased TNF production [30]. (4) APP or Aβ reduce Cu²⁺ to Cu⁺—this redox cycling promotes production of ROS including H₂O₂. (5) NK cell-derived IFNγ can increase Cu uptake in microglia via enhanced CTR1 expression [27]. IFNγ also promotes ATP7A elevation and vesicular trafficking. These mechanisms of Cu sequestration by microglia may prevent further plaque formation. Phagocytosis of amyloid plaques also raises microglial Cu levels and promotes Aβ clearance. (6) Cu may polarize inflamed microglial populations from the neurotoxic (M1) phenotype to the neuroprotective (M2) phenotype via inhibition of NO production [31]. (7) The Fe master regulator, hepcidin, is induced by cytokines in AD and prevents Fe release from neurons. Excess Fe binds IREs in the APP promoter and upregulates APP production, promoting Cu export and mislocalisation.