Neuroinflammation and copper in Alzheimer's disease

Abstract

Inflammation is the innate immune response to infection or tissue damage. Initiation of proinflammatory cascades in the central nervous system (CNS) occurs through recognition of danger associated molecular patterns by cognate immune receptors expressed on inflammatory cells and leads to rapid responses to remove the danger stimulus. The presence of activated microglia and astrocytes in the vicinity of amyloid plaques in the brains of Alzheimer's disease (AD) patients and mouse models implicates inflammation as a contributor to AD pathogenesis. Activated microglia play a critical role in amyloid clearance, but chronic deregulation of CNS inflammatory pathways results in secretion of neurotoxic mediators that ultimately contribute to neurodegeneration in AD. Copper (Cu) homeostasis is profoundly affected in AD, and accumulated extracellular Cu drives A β aggregation, while intracellular Cu deficiency limits bioavailable Cu required for CNS functions. This review presents an overview of inflammatory events that occur in AD in response to A β and highlights recent advances on the role of Cu in modulation of beneficial and detrimental inflammatory responses in AD.

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.

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.