Per-6-substituted β-cyclodextrin libraries inhibit formation of β-amyloid-peptide (Aβ)-derived, soluble oligomers

Abstract

Alzheimer's disease is the most common cause of dementia in older individuals with compelling evidence favoring neuron dysfunction and death triggered by assembled forms of A beta(1-42). While large neurotoxic amyloid fibrils have been known for years, recent studies show that soluble protofibril and A beta(1-42)-derived diffusible ligands (ADDLs) may also be involved in neurotoxicity. In the present work, dot-blot immunoassays discriminating ADDLs from monomers were used to screen libraries of per-substituted beta-cyclodextrin (beta-CD) derivatives for inhibition of ADDLs formation. Libraries were prepared from per-6-iodo-beta-CD by treatment with various amine nucleophiles. The most active library tested (containing >2000 derivatives) was derived from imidazole, N, N-dimethylethylenediamine and furfurylamine, which at 10 microM total library, inhibited ADDLs formation (10 nM A beta(1-42)) over a period of 4 hours. The latter was confirmed by a western blot assay showing decreased amounts of the initially formed A beta(1-42) tetramer. These preliminary experiments suggest that derivatized forms of beta-CD can interfere with the oligomerization process of A beta(1-42).

The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in Alzheimers Disease

“…These efforts are aided by the development of more specific reagents (e.g., antibodies as described above) that enable higher efficiency screening of compound collections. Recent manuscripts by Venton and colleagues have detailed the identification and preparation of a series of per-6-amino-6-deoxy-β-cyclodextrins as blockers of ADDL assembly [161,162]. Further, a series of di-and tri-substituted aromatic compounds have recently been described that appear to block ADDL oligomerization more efficiently than fibrilization.…”

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]. Based on this ability of CD to form a complex with Aβ and aiming at inhibiting amyloid fibril formation, mucoadhesive microspheres made of chitosan or alginate and containing β-CDs (either native β-CD or HPβCD) were developed as drug candidates in a nasal delivery system for brain targeting [72].…”

Towards a Unifying Hypothesis of Alzheimers Disease: Cholinergic System Linked to Plaques, Tangles and Neuroinflammation

“…But once it forms stable network then even 1.3 GPa pressure was not able to dissociate the nano-ordered assemblies, indicating that these peptides are now bound together and stabilized by stronger covalent forces [92]. In addition, many of the inhibitors (CR, thioflavin T and S, galantamine, polyphenols, cyclodextrin derivatives [94], 2,4-dinitrophenols [95], imatinib mesylate [96], binapthyl derivatives [97], etc.) of βA aggregation (Figs.…”