Alzheimer's

The Cu(II)/Abeta/human serum albumin model of control mechanism for copper-related amyloid neurotoxicity.

Chem Res Toxicol. 2010 Feb 15;23(2):298-308.

Rózga M, Bal W.

Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland.

Abstract

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 Abeta peptides in the pathogenesis of AD, but exact mechanisms of Abeta toxicity remain unclear. Recently, evidence has accumulated in favor of small oligomers of the Abeta42 peptide as major toxic species. Metal ions, copper(II) in particular, have been implicated in molecular mechanisms of Abeta neurotoxicity, including oxidative damage of lipid membranes. While monomeric Abeta peptides are not neurotoxic, the deep understanding of their chemical properties is prerequisite for significant progress in Alzheimer research. Monomeric Abeta40 and Abeta42 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 Abeta 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 Abeta molecule with a moderate, micromolar affinity. In this <leo_highlight style="border-bottom: 2px solid #ffff96; background: transparent none repeat scroll 0% 50%; cursor: pointer; display: inline;" id="leoHighlights_Underline_0" on-click="leoHighlightsHandleClick('leoHighlights_Underline_0')" on-mouseover="leoHighlightsHandleMouseOver('leoHighlights_Underline_0')" on-mouseout="leoHighlightsHandleMouseOut('leoHighlights_Underline_0')" leohighlights_keywords="perspective" leohighlights_url_top="http%3A//shortcuts.thebrowserhighlighter.com/leonardo/plugin/highlights/3_1/tbh_highlightsTop.jsp?keywords%3Dperspective%26domain%3Dwww.ncbi.nlm.nih.gov" leohighlights_url_bottom="http%3A//shortcuts.thebrowserhighlighter.com/leonardo/plugin/highlights/3_1/tbh_highlightsBottom.jsp?keywords%3Dperspective%26domain%3Dwww.ncbi.nlm.nih.gov" leohighlights_underline="true">perspective, we present a model of interactions, which make HSA a likely guardian against Cu/Abeta toxicity in extracellular brain compartments.