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

Abstract

Amyloid-beta peptides (Abeta) 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 Abeta and copper ions have been proposed to be an aberrant interaction implicated in the development of Alzheimer's disease, where Cu is involved in Abeta aggregation and production of reactive oxygen species (ROS). In the present work, we studied copper-exchange reaction between Abeta and HSA or the tetrapeptide DAHK (N-terminal Cu-binding domain of HSA) and the consequence of this exchange on Abeta-induced ROS production and cell toxicity. The following results were obtained: 1) HSA and DAHK removed Cu(II) from Abeta rapidly and stoichiometrically, 2) HSA and DAHK were able to decrease Cu-induced aggregation of Abeta, 3) HSA and DAHK suppressed the catalytic HO(.) production in vitro and ROS production in neuroblastoma cells generated by Cu-Abeta and ascorbate, 4) HSA and DAHK were able to rescue these cells from the toxicity of Cu-Abeta 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)-Abeta interaction. The repercussion of the competition between HSA and Abeta to bind Cu in the blood and brain and its relation to Alzheimer's disease are discussed.

Human Serum Albumin Can Regulate Amyloid-β Peptide Fiber Growth in the Brain Interstitium

“…Albumin is also responsible for the transport of the labile pool of Cu 2ϩ ions in blood plasma (21). Of note, the A␤-Cu 2ϩ interaction and its role in AD have received significant interest (22)(23)(24), and Cu 2ϩ may be transferred from A␤ to HSA (25), meaning that albumin could have two mechanisms by which it inhibits fiber formation.…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Toxicity of Aβ oligomers can be attenuated in cultures by copper chelation [176,177]. The mechanism of copper-Aβ induced cytotoxicity might involve oxidative stress, as the complex catalytically generates hydrogen peroxide [178][179][180].…”

Thermodynamic study of Cu2+ binding to the DAHK and GHK peptides by isothermal titration calorimetry (ITC) with the weaker competitor glycine

“…It was also determined that DAHK prevents lipid oxidation in a copper-catalyzed oxidant system [14]. The DAHK peptide as well as HSA was shown to be able to remove copper rapidly and stoichiometrically from Aβ, to restrict Aβ aggregation, to suppress the catalytic ROS production and to reduce neurotoxicity [15].…”

“…This tripeptide also actively participates in the processes of wound healing and tissue repair [16]. It was also reported to compete successfully with Aβ for Cu 2+ coordination, thus being able to act as a potential protector from Cu-Aβ toxicity [12,15,18].…”