Specific Binding of a β-Cyclodextrin Dimer to the Amyloid β Peptide Modulates the Peptide Aggregation Process

Abstract

Alzheimer's disease involves progressive neuronal loss. Linked to the disease is the amyloid β (Aβ) peptide, a 38-43-amino acid peptide found in extracellular amyloid plaques in the brain. Cyclodextrins are nontoxic, cone-shaped oligosaccharides with a hydrophilic exterior and a hydrophobic cavity making them suitable hosts for aromatic guest molecules in water. β-Cyclodextrin consists of seven α-d-glucopyranoside units and has been shown to reduce the level of fibrillation and neurotoxicity of Aβ. We have studied the interaction between Aβ and a β-cyclodextrin dimer, consisting of two β-cyclodextrin monomers connected by a flexible linker. The β-cyclodextrin monomer has been found to interact with Aβ(1-40) at sites Y10, F19, and/or F20 with a dissociation constant (K(D)) of 3.9 ± 2.0 mM. Here (1)H-(15)N and (1)H-(13)C heteronuclear single-quantum correlation nuclear magnetic resonance (NMR) spectra show that in addition, the β-cyclodextrin monomer and dimer bind to the histidines. NMR translational diffusion experiments reveal the increased affinity of the β-cyclodextrin dimer (apparent K(D) of 1.1 ± 0.5 mM) for Aβ(1-40) compared to that of the β-cyclodextrin monomer. Kinetic aggregation experiments based on thioflavin T fluorescence indicate that the dimer at 0.05-5 mM decreases the lag time of Aβ aggregation, while a concentration of 10 mM increases the lag time. The β-cyclodextrin monomer at a high concentration decreases the lag time of the aggregation. We conclude that cyclodextrin monomers and dimers have specific, modulating effects on the Aβ(1-40) aggregation process. Transmission electron microscopy shows that the regular fibrillar aggregates formed by Aβ(1-40) alone are replaced by a major fraction of amorphous aggregates in the presence of the β-cyclodextrin dimer.

Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases

“…Additionally, β-CDs have been reported to be able to directly bind Aβ [69][70][71], and substantially decrease its neurotoxic effect in vitro. Another β-CD derivative, the per-6-alkylamino-β-CD, has been shown to interfere with the oligomerization process of Aβ 1-42 responsible in part for Aβ neurotoxicity [79].…”

Cyclodextrin 3‐Functionalized with 8‐Hydroxyquinoline as an Antioxidant Inhibitor of Metal‐Induced Amyloid Aggregation

“…The neuroprotection by CyD has been reported in vivoi n the case of neurodegenerative diseases. [14] In particular, b-CyD is able to interact with Ab 1-40 amyloid peptide at sites Y10, F19, and/or F20 [15] and decrease substantially the neurotoxic effects of Ab in vitro [16,17] and in vivo. [18] Interestingly, b-CyD acts in synergyw ith curcumin to suppress a-synuclein aggregation (involved in Parkinson's disease) and breaks up the preformed aggregates almost completely.…”

Halogenation Generates Effective Modulators of Amyloid-Beta Aggregation and Neurotoxicity

“…According to the revised amyloid-cascade hypothesis, certain types of soluble Aβ oligomers and protofibrils are more toxic than Aβ fibrils and correlate well with dementia [14], [15], [16], [17]. Therefore, modulation of Aβ aggregation using small molecules is considered a promising way to eliminate Aβ associated toxicity [3], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. We recently reported that red food dye erythrosine B (ERB) is a novel modulator of Aβ-aggregation in vitro and Aβ neurotoxicity [33].…”