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

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[HAsVMoV6MoVI6O40] [CAM, L = 2-(1H-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 e-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 ...