Copper imbalance in Alzheimer's disease: Overview of the exchangeable copper component in plasma and the intriguing role albumin plays

Essential metals are vital elements for human biology. Iron, copper, and zinc are all essential for life. Trace metal dyshomeostasis has been linked to cognitive deterioration and in particular to a disturbance in the regulation of copper (Cu), characterized by an increase in serum Cu not bound to ceruloplasmin (nCp-Cu also known as "free" copper). It is thought to play a role in the development of Alzheimer's disease (AD), the most common form of dementia. Copper homeostasis is finely regulated in our bodies and the expansion of exchangeable nCp-Cu is symptom of the breakdown of this homeostasis, which affects myriad biological pathways. If not structurally bound to enzymes or coordinated by proteins, copper generates free radicals via Haber-Weiss and Fenton reactions. Human Serum Albumin (HSA) is the most abundant serum protein and the main protein exchanging copper in the nCp-Cu pool. Copper coordinated by HSA is in equilibrium with copper coordinated by other small copper chelators circulating in the blood stream in a dynamic and exchangeable manner dependent on environmental osmolarity, oxidation state, pH and compounds' functions. Albumin is susceptible to glycation starting from Maillard reaction, carbohydrates, in particular glucose, form advanced glycation end-products (AGEs). AGE-albumin is one of this products. Free radicals and free metals in circulation accelerate this cross-linking of protein with carbohydrates. Modified albumins are also significantly less effective than native forms in avoiding the aggregation of A beta, the main component of the amyloid plaques in the AD brain. The current review aims to provide insight into the coordination chemistry of copper in plasma with a special glance toward the exchangeable copper coordinated by albumin, to explore how aberrant regulations of this interaction are linked to the aetiology of AD. (C) 2018 Elsevier B.V. All rights reserved.