Copper transfer from Cu-Abeta to human serum albumin inhibits aggregation, radical production and reduces Abeta toxicity.
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.
Perrone
Lorena
L
CNRS UMR 5089, Institut de Pharmacologie et de Biologie Structurale, 205 route de Narbonne, Toulouse, France.
Mothes
Emmanuelle
E
Vignes
Maeva
M
Mockel
Anaïs
A
Figueroa
Cindy
C
Miquel
Marie-Christine
MC
Maddelein
Marie-Lise
ML
Faller
Peter
P
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D017209:Apoptosis; D001205:Ascorbic Acid / Q000378:metabolism; D045744:Cell Line, Tumor; D003300:Copper / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D046529:Microscopy, Electron, Transmission; D009391:Nephelometry and Turbidimetry; D010455:Peptides / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010455:Peptides; D017382:Reactive Oxygen Species; D012709:Serum Albumin; D003300:Copper; D001205:Ascorbic Acid