Alzheimer's disease (AD) is the most common form of neurodegenerative disease. The brain is particularly vulnerable to oxidative damage induced by unregulated redox-active metals such as copper and iron, and the brains of AD patients display evidence of metal dyshomeostasis and increased oxidative stress. The colocalisation of copper and amyloid beta (Abeta) in the glutamatergic synapse during NMDA-receptor-mediated neurotransmission provides a microenvironment favouring the abnormal interaction of redox-potent Abeta with copper under conditions of copper dysregulation thought to prevail in the AD brain, resulting in the formation of neurotoxic soluble Abeta oligomers. Interactions between Abeta oligomers and copper can further promote the aggregation of Abeta, which is the core component of extracellular amyloid plaques, a central pathological hallmark of AD. Copper dysregulation is also implicated in the hyperphosphorylation and aggregation of tau, the main component of neurofibrillary tangles, which is also a defining pathological hallmark of AD. Therefore, tight regulation of neuronal copper homeostasis is essential to the integrity of normal brain functions. Therapeutic strategies targeting interactions between Abeta, tau and metals to restore copper and metal homeostasis are discussed.

Over the past two decades there have been significant advances in our understanding of copper homeostasis and the pathological consequences of copper dysregulation. Cumulative evidence is revealing a complex regulatory network of proteins and pathways that maintain copper homeostasis. The recognition of copper dysregulation as a key pathological feature in prominent neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and prion diseases has led to increased research focus on the mechanisms controlling copper homeostasis in the brain. The copper-transporting P-type ATPases (copper-ATPases), ATP7A and ATP7B, are critical components of the copper regulatory network. Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993. They are large polytopic transmembrane proteins with six copper-binding motifs within the cytoplasmic N-terminal domain, eight transmembrane domains, and highly conserved catalytic domains. These proteins catalyze ATP-dependent copper transport across cell membranes for the metallation of many essential cuproenzymes, as well as for the removal of excess cellular copper to prevent copper toxicity. A key functional aspect of these copper transporters is their copper-responsive trafficking between the trans-Golgi network and the cell periphery. ATP7A- and ATP7B-deficiency, due to genetic mutation, underlie the inherited copper transport disorders, Menkes and Wilson diseases, respectively. Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders. Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration.

Accumulation of the amyloid ␤ peptide in the cortical and hippocampal regions of the brain is a major pathological feature of Alzheimer disease. Amyloid ␤ peptide is generated from the sequential protease cleavage of the amyloid precursor protein (APP). We reported previously that copper increases the level of APP at the cell surface. Here we report that copper, but not iron or zinc, promotes APP trafficking in cultured polarized epithelial cells and neuronal cells. In SH-SY5Y neuronal cells and primary cortical neurons, copper promoted a redistribution of APP from a perinuclear localization to a wider distribution, including neurites. Importantly, a change in APP localization was not attributed to an up-regulation of APP protein synthesis. Using live cell imaging and endocytosis assays, we found that copper promotes an increase in cell surface APP by increasing its exocytosis and reducing its endocytosis, respectively. This study identifies a novel mechanism by which copper regulates the localization and presumably the function of APP, which is of major significance for understanding the role of APP in copper homeostasis and the role of copper in Alzheimer disease. The neuropathology of Alzheimer disease (AD)3 includes the accumulation of extracellular plaques containing amyloid ␤ peptide (A␤) in the cortical and hippocampal regions of the brain, intracellular neurofibrillary tangles, and trace metal dyshomeostasis. The trace metals copper, zinc, and iron are significantly enriched in the amyloid plaques of AD patients compared with age-matched subjects (1, 2). Interaction between A␤ and copper or zinc promotes peptide oligomerization and aggregation, eventually leading to further amyloid deposition (3-7). In addition, A␤ is able to catalyze the reduction of Cu(II) and Fe(III), generating reactive oxygen species that contribute to the oxidative stress observed in the AD brain (8 -14). Paradoxically, there is evidence of copper deficiency in neighboring cells (15-18), compromising the activity of copper-dependent enzymes, such as cytochrome c-oxidase and copper/zinc-superoxide dismutase (SOD1), which are essential for cellular respiration and as antioxidant defense, respectively (19 -21). Restoration of copper balance using ionophores (22), such as clioquionol and PBT-2, has shown promising results in both animal and human trials (23)(24)(25)(26). A proposed mechanism of action of these drugs is to bind to extracellular copper and restore intracellular copper levels, hence correcting copper dyshomeostasis. Importantly, these ionophores are capable of reducing amyloid load and attenuate cognitive decline (23-26).Amyloid precursor protein (APP) is differentially processed by the ␣-, ␤-, and ␥-secretases in two alternative processing pathways, commonly referred to as the nonamyloidogenic and amyloidogenic pathways (supplemental Fig. S1). In the non-amyloidogenic pathway, APP is initially cleaved by an ␣-secretase that is predominantly localized to the plasma membrane (27, 28), generating an N-terminal ectodomain (s...