Alzheimer's Aβ40 Studied by NMR at Low pH Reveals That Sodium 4,4-Dimethyl-4-silapentane-1-sulfonate (DSS) Binds and Promotes β-Ball Oligomerization

The Alzheimer's Aβ40 peptide forms soluble oligomers that are extremely potent neurotoxins and strongly impede synapses function. In this study the formation and structure of the large, soluble, neurotoxic Aβ40 oligomer called “β-ball” were characterized by two-dimensional NMR, circular dichroism, fluorescence spectroscopy, hydrogen exchange, and equilibrium sedimentation. In acidic aqueous solution, half the Aβ40 molecules are in the β-ball state; the remainder are monomeric. The equilibrium between the two states is slow as judged by NMR linewidths and is stable for months. The kinetics of β-ball formation from monomer are biphasic with τ1 = 7 min and τ2 = 80 min with no transient helix formation. Monomeric Aβ40 is essentially devoid of stable secondary structure, although the central, Leu17–Ala21, and C-terminal, Gly29–Val40, hydrophobic regions show propensity toward adopting extended structure, and residues 22–25 tended to form a turn. We found that sodium 4,4-dimethyl-4-silapentane-1-sulfonate (DSS) binds to the central hydrophobic region of monomeric Aβ40. DSS binds β-balls more strongly and caused them to double in size. Plausible micelle-like models for the β-ball structure with and without bound DSS are presented. The Alzheimer's Aβ40 peptide forms soluble oligomers that are extremely potent neurotoxins and strongly impede synapses function. In this study the formation and structure of the large, soluble, neurotoxic Aβ40 oligomer called “β-ball” were characterized by two-dimensional NMR, circular dichroism, fluorescence spectroscopy, hydrogen exchange, and equilibrium sedimentation. In acidic aqueous solution, half the Aβ40 molecules are in the β-ball state; the remainder are monomeric. The equilibrium between the two states is slow as judged by NMR linewidths and is stable for months. The kinetics of β-ball formation from monomer are biphasic with τ1 = 7 min and τ2 = 80 min with no transient helix formation. Monomeric Aβ40 is essentially devoid of stable secondary structure, although the central, Leu17–Ala21, and C-terminal, Gly29–Val40, hydrophobic regions show propensity toward adopting extended structure, and residues 22–25 tended to form a turn. We found that sodium 4,4-dimethyl-4-silapentane-1-sulfonate (DSS) binds to the central hydrophobic region of monomeric Aβ40. DSS binds β-balls more strongly and caused them to double in size. Plausible micelle-like models for the β-ball structure with and without bound DSS are presented. Amyloid plaques, one of two classic histological hallmarks of Alzheimer's disease (1Gorman P.M. Chakrabartty A. 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