Copper and Alzheimer disease: The good, the bad and the ugly

Abstract

Copper is vital to normal brain function; but its potent redox activity demands tight regulation to maintain the integrity of copper homeostasis. Disrupted regulation can result in copper displacement, causing inadvertent interactions between copper and cellular components, which can enhance the production of reactive oxygen species (ROS), formation of neurotoxic copper-protein aggregates, and eventually, neuronal cell death. Disrupted copper homeostasis is a feature common to many neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease, Wilson's disease, Menkes disease and prion disease. This review focuses on the involvement of copper in AD. An intrinsic reciprocal relationship exists between copper and AD-associated proteins, amyloid precursor protein (APP) and BACE1. Under conditions of copper dysregulation, the postsynaptic release of both copper and AB into the synaptic cleft of glutamatergic neurons promotes the abnormal interaction of redox-active Aß with copper, forming neurotoxic soluble AB oligomers. A cascade of Aß aggregation ensues, resulting in extracellular amyloid plaques, a pathological hallmark of AD. Additionally, copper also participates in the aggregation of tau, the core component of neurofibrillary tangles, which is the other defining pathology of AD brains. Therapeutic strategies targeting interactions among AB, tau and metals to restore copper and metal balance have disease-modifying promise.