The Cu(II)/Aβ/Human Serum Albumin Model of Control Mechanism for Copper-Related Amyloid Neurotoxicity

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly population, above 65 years of age. Multiple lines of evidence confirm the central role of 40-42 residue A beta peptides in the pathogenesis of AD, but exact mechanisms of A beta toxicity remain unclear. Recently, evidence has accumulated in favor of small oligomers of the A beta 42 peptide as major toxic species. Metal ions, copper(II) in particular, have been implicated in molecular mechanisms of A beta neurotoxicity, including oxidative damage of lipid membranes. While monomeric A beta peptides are not neurotoxic, the deep understanding of their chemical properties is prerequisite for significant progress in Alzheimer research. Monomeric A beta 40 and A beta 42 form a specific mononuclear complex with Cu(II), recruiting donor atoms within their common 16 amino acid N-terminal sequence. The formation of this complex, the exact structure of which is debated, correlates with increased A beta toxicity. Human serum albumin (HSA) is a versatile carrier protein present, among others, in blood and cerebrospinal fluid. It binds one Cu(II) ion with a high, picomolar affinity and one A beta molecule with a moderate, micromolar affinity. In this perspective, we present a model of interactions, which make HSA a likely guardian against Cu/A beta toxicity in extracellular brain compartments.