Structure and mechanism behind the inhibitory effect of water soluble metalloporphyrins on Aβ1–42 aggregation

Abstract

Although the exact molecular mechanism of the pathogenesis of Alzheimer's disease (AD) is still unclear, compounds that can inhibit the aggregation of amyloid-β peptide (Aβ_1–42) or scavenge the highly toxic peroxynitrite (ONOO⁻) free radical have been confirmed to delay or alleviate AD to a certain extent. Thus, the design and screening of dual-function compounds are important for biomedical aims. A group of water soluble metallopophyrins, including FeTMPyP, MnTMPyP, FeTBAP and MnTBAP, are well known active ONOO⁻ decomposition catalysts, which share the structural similarity of planar aromatic conjugation with a valuable class of inhibitors against amyloid fibrillation, although their effects on Aβ_1–42 aggregation and toxicity have been less explored. Here, we aimed to investigate their inhibitory effects on Aβ_1–42 aggregation, in particular, how this relates to the structure. Fluorescence and TEM results showed that cationic metalloporphyrins (FeTMPyP and MnTMPyP) exhibited a stronger inhibitory effect on Aβ_1–42 fibrillation than anionic metalloporphyrins (FeTBAP and MnTBAP), and the metalloporphyrin with an iron center is more effective than the one with a manganese center. Cell experiments revealed that the protective effect of these metalloporphyrins on Aβ_1–42-induced cytotoxicity is consistent with their anti-fibrillization activity. We also provide evidence that metalloporphyrins stabilize the Aβ_1–42 monomer, resulting in interfering with its self-assembly. The electrostatic interaction between the tetraphenylporphyrin of a metalloporphyrin and an amyloid peptide determines the inhibitory effect of metalloporphyrins. However, for the same ligand porphyrin, Fe-porphyrin is more effective than Mn-porphyrin, which can be attributed to the additional coordination bond between the central metal atom (Fe) and the amyloid peptide. The conclusions were further confirmed by the use of another amyloid polypeptide (hIAPP) and other anionic metalloporphyrins (FeTPPS and MnTPPS). We believe that the findings will aid in the development of metalloporphyrin agents targeting AD and other amyloid diseases.