期刊
CHEMICAL RESEARCH IN TOXICOLOGY
卷 23, 期 2, 页码 298-308出版社
AMER CHEMICAL SOC
DOI: 10.1021/tx900358j
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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.
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