Lipid-Induced Conformational Transition of Amyloid β Peptide Fragments

Abstract

Conformational transition of soluble monomeric amyloid beta-peptide (Abeta) into oligomeric and protofibrillar aggregates plays a key role in the pathogenesis of Alzheimer's disease (AD). One of the central questions surrounding the molecular pathophysiology of AD is how the soluble Abeta is converted into its aggregated toxic form. A more detailed understanding of the conformational transitions involved in the self-assembly of Abeta may facilitate the design of inhibitors of aggregation. In this study, we evaluated the wild-type (WT) Abeta 16-28 peptide (KLVFFAEDVGSNK) and its associated mutants, including A21G (Flemish), E22K (Italian), E22Q (Dutch), and E22G (Arctic) mutants, by examining, in particular, their aggregation kinetics in the presence and in the absence of negatively charged and zwitterionic lipids. Circular dichroic and thioflavin T fluorescence studies indicated that the WT peptide undergoes a rapid conformational transition into beta-sheet structure in solution, whereas the Arctic and Dutch variants show a markedly rapid transition into beta-sheet structure in the presence of negatively charged lipids. These results provide strong evidence suggesting that the reduction in net charge, with a concurrent increase in the net hydrophobicity of the peptide alone or when complexed with lipid in solution, determines the rate of aggregate formation.

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

“…in affecting the binding and oligomerization of Ab is being increasingly examined (Kayed et al 2009;Salay et al 2009;Kotarek and Moss 2010;Sureshbabu et al 2010). Smaller (1-2 nm diameter) synthetic Ab oligomers have a greater tendency to bind such charged species than do those of larger (4-5 nm) size (Cizas et al 2010).…”

Autophagy-Derived Alzheimer’s Pathogenesis

“…This membrane disruption is thought to result from the direct interaction between the hydrophobic C-terminus of Aβ peptides and the lipid bilayer of the membrane (Marchesi, 2005). The interaction also appears to be important for membrane-associated Aβ assembly into higher ordered structures (Friedman et al, 2009;Sureshbabu et al, 2010). Compromised membrane integrity greatly increases membrane conductance that has been attributed to a putative ionic channel formed by Aβ peptides (Jang et al, 2010).…”

Assembly of Amyloid β-Protein Variants Containing Familial Alzheimer’s Disease-Linked Amino Acid Substitutions

“…Sureshbabu et al [31] have suggested that, in the absence of other potentially confounding local environmental factors, mutations resulting in the loss of negative charge in Aβ facilitate aggregation [40] due to a decrease in the electrostatic repulsion among monomers [41]. Sureshbabu et al [31] have suggested that, in the absence of other potentially confounding local environmental factors, mutations resulting in the loss of negative charge in Aβ facilitate aggregation [40] due to a decrease in the electrostatic repulsion among monomers [41].…”

“…The Italian mutation in Aβ42 leads to increased toxicity in rat pheochromocytoma (PC-12) cells using the MTT assay [34] or primary cultured human cerebrovascular smooth muscle cells measured by the fluorescent Live/Dead cell assay [67] compared to WT Aβ42. The Italian Aβ variant has been reported to be among the fastest and among the slowest aggregators [31,32]. The Italian Aβ variant has been reported to be among the fastest and among the slowest aggregators [31,32].…”