Modulating Conformation of Aβ-Peptide: An Effective Way to Prevent Protein-Misfolding Disease

Abstract

Alzheimer's disease (AD) is a typical protein-misfolding disease. Aggregation of amyloid β-peptide (Aβ) plays a key role in the etiology of AD. The misfolding of Aβ results in the formation of β-sheet-rich aggregates and damages the function of neurons. A modified polyoxometalate (POM), [CoL(H₂O)]₂[CoL]₂[HAs^VMo^V₆Mo^VI₆O₄₀] [CAM, L = 2-(1 H-pyrazol-3-yl)pyridine], was designed to disaggregate the Aβ aggregates, where L acts as an Aβ-targeting group and POM as a conformational modulator. X-ray crystallography shows that CAM is composed of a ε-Keggin unit and four coordination units. CAM can disaggregate the β-sheet-rich fibrils and metal-induced or self-aggregated Aβ aggregates, and it further inhibits the production of ROS; as a result, it can protect the neurons from synaptic toxicity induced by Zn²⁺- or Cu²⁺-Aβ aggregates or Aβ self-aggregation. The mechanism of disaggregation involves a transformation of Aβ conformation from β-sheet to other conformers. The nature of the process is an interference of the β-sheet conformation by CAM via hydrogen bonding. CAM specifically interacts with Aβ aggregates but does not disturb the cerebral metal homeostasis and enzymatic systems. Molecular simulation suggests that the appropriate size of CAM and the cavity of β-sheets facilitate the interaction between CAM and Aβ aggregates; additionally, the H-bonding-favored amino acid residues in the cavity provide a precondition for the interaction. Moreover, CAM is lipophilic and capable of penetrating the blood-brain barrier, and it is metabolizable without causing an untoward effect to mice at high dosages. In view of the significant inhibitory effect on the Aβ aggregation and related neurotoxicity, CAM represents a new type of leading compounds with a distinctive mechanism of action for the treatment of Alzheimer' disease. The conception of this study may be applied to other protein-misfolding diseases caused by conformational changes.