Copper in Brain and Neurodegeneration

Abstract

Abstract Cu is an essential element for the brain. It is involved in neurotransmission and is required for several cuproenzymes of the brain. Cu deficiency and Cu excess are associated with Menkes disease and Wilson's disease, respectively, and the importance of Cu in the brain is amply illustrated by the severe neurological symptoms elicited by these diseases. Disruption of Cu homeostasis is also evident in complex neurodegenerative diseases and is implicated in their pathogenesis. Cu influences the regulation and aggregation of key Alzheimer's disease ( AD ) neuropathological proteins such as amyloid precursor protein, amyloid‐β, and tau. Parkinson's disease ( PD ) is associated with a decreased Cu content of the substantia nigra, the brain region that is affected in the disease. Cu also promotes the aggregation of α‐synuclein, the predominant protein present in the characteristic Lewy bodies of PD brain, and huntingtin, found in inclusions in Huntington's disease. Mutant SOD1 is thought to have a toxic gain of function in amyotrophic lateral sclerosis, possibly caused by Zn‐deficient CuSOD1 . Niemann‐Pick type C disease ( NPC ) is caused by mutations in the NPC gene, giving rise to impaired NPC protein. Evidence suggests that NPC may be involved in Cu metabolism. The involvement of Cu in these diseases is highlighted by the efficacy of therapeutics targeting the redistribution of Cu. Cu ionophores such as clioquinol and PBT2 bind endogenous Cu, transport it into cells and induce multiple cellular pathways. In AD , these ionophores likely sequester Cu bound to amyloid‐β plaques. Preformed bis(thiosemicarbazone)‐Cu complexes deliver exogenous Cu into the brain and induce similar pathways to the ionophores. These Cu complexes have shown efficacy in animal models of several neurodegenerative diseases, and the cellular pathways induced are being elucidated. These therapeutic outcomes, together with improved resolution of techniques for identifying Cu distribution in brain cells, are providing valuable new insights into the role of Cu in neuronal and glial cell homeostasis.