Copper Transfer from Cu–Aβ to Human Serum Albumin Inhibits Aggregation, Radical Production and Reduces Aβ Toxicity

Amyloid-b peptides (Ab) and the protein human serum albumin (HSA) interact in vivo. They are both localised in the blood plasma and in the cerebrospinal fluid. Among other functions, HSA is involved in the transport of the essential metal copper. Complexes between Ab and copper ions have been proposed to be an aberrant interaction implicated in the development of Alzheimer’s disease, where Cu is involved in Ab aggregation and production of reactive oxygen species (ROS). In the present work, we studied copper-exchange reaction between Ab and HSA or the tetrapeptide DAHK (N-terminal Cu-binding domain of HSA) and the consequence of this exchange on Abinduced ROS production and cell toxicity. The following results were obtained: 1) HSA and DAHK removed Cu II from Ab rapidly and stoichiometrically, 2) HSA and DAHK were able to decrease Cu-induced aggregation of Ab, 3) HSA and DAHK suppressed the catalytic HOC production in vitro and ROS production in neuroblastoma cells generated by Cu–Ab and ascorbate, 4) HSA and DAHK were able to rescue these cells from the toxicity of Cu–Ab with ascorbate, 5) DAHK was more potent in ROS suppression and restoration of neuroblastoma cell viability than HSA, in correlation with an easier reduction of Cu II –HSA than Cu–DAHK by ascorbate, in vitro. Our data suggest that HSA is able to decrease aberrant Cu II –Ab interaction. The repercussion of the competition between HSA and Ab to bind Cu in the blood and brain and its relation to Alzheimer’s disease are discussed.