Alzheimer's disease (AD) is a typical protein-misfolding disease. Aggregation of amyloid beta-peptide (A beta) plays a key role in the etiology of AD. The misfolding of A beta results in the formation of beta-sheet-rich aggregates and damages the function of neurons. A modified polyoxometalate (POM), [CoL(H2O)](2)[CoL]2[(HAsMo6O40)-Mo-V-O-VI] [CAM, L = 2-(1H-pyrazol-3-yl)pyridine], was designed to disaggregate the A beta aggregates, where L acts as an A beta-targeting group and POM as a conformational modulator. Xray crystallography shows that CAM is composed of a epsilon-Keggin unit and four coordination units. CAM can disaggregate the beta-sheet-rich fibrils and metal induced or self-aggregated A beta 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+-A beta aggregates or A beta self-aggregation. The mechanism of disaggregation involves a transformation of Afi conformation from beta-sheet to other conformers. The nature of the process is an interference of the beta-sheet conformation by CAM via hydrogen bonding. CAM specifically interacts with A beta 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 beta-sheets facilitate the interaction between CAM and Afi 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 Al 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.