ic8b02115_si_001.pdf (839.96 kB)
Modulating Conformation of Aβ-Peptide: An Effective Way to Prevent Protein-Misfolding Disease
journal contribution
posted on 2018-10-19, 21:45 authored by Xiang Ma, Jiai Hua, Kun Wang, Hongmei Zhang, Changli Zhang, Yafeng He, Zijian Guo, Xiaoyong WangAlzheimer’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 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.