Dataset Information

TMPyP Inhibits Amyloid-? Aggregation and Alleviates Amyloid-Induced Cytotoxicity.

ABSTRACT: The aggregation or misfolding of amyloid-? (A?) is a major pathological hallmark of Alzheimer's disease (AD). The regulation of A? aggregation is thought to be an effective strategy for AD treatment. The capability of a water-soluble porphyrin, 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP), to inhibit A? aggregation and to lower A?-induced toxicity was demonstrated. As evidenced by surface plasmon resonance and circular dichroism, TMPyP can not only disrupt A? aggregation but also disassemble the preformed A? aggregates. The atomic force microscopy imaging proves that TMPyP inhibits the formation of both oligomers and fibrils. Molecular dynamic simulations provide an insight into the interaction between TMPyP and A? at the molecular level. The half-maximal inhibitory concentrations of TMPyP acting on the oligomers and fibrils were determined to be 0.6 and 0.43 ?M, respectively. As a member of porphyrin family, TMPyP is of rather low cytotoxicity, and the cytotoxicity of the A? aggregates was also relieved upon coincubation with TMPyP. The excellent performance of TMPyP thus makes it a potential drug candidate for AD therapy.

SUBMITTER: Fan Y

PROVIDER: S-EPMC6044923 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Publications

TMPyP Inhibits Amyloid-β Aggregation and Alleviates Amyloid-Induced Cytotoxicity.

Fan Yujuan Y Wu Daohong D Yi Xinyao X Tang Hailin H Wu Ling L Xia Yonghong Y Wang Zixiao Z Liu Qiuhua Q Zhou Zaichun Z Wang Jianxiu J

ACS omega 20170803 8

The aggregation or misfolding of amyloid-β (Aβ) is a major pathological hallmark of Alzheimer's disease (AD). The regulation of Aβ aggregation is thought to be an effective strategy for AD treatment. The capability of a water-soluble porphyrin, 5,10,15,20-tetrakis(<i>N</i>-methyl-4-pyridyl)porphyrin (TMPyP), to inhibit Aβ aggregation and to lower Aβ-induced toxicity was demonstrated. As evidenced by surface plasmon resonance and circular dichroism, TMPyP can not only disrupt Aβ aggregation but a ...[more]

PMID: 30023716

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Project description:Complement inhibitor C4b-binding protein (C4BP) is synthesized in liver and pancreas and composed of 7 identical alpha chains and one unique beta chain. We showed previously that C4BP binds islet amyloid polypeptide (IAPP) and affects fibril formation in vitro. Now we found that polymeric C4BP inhibited lysis of human erythrocytes incubated with monomeric IAPP while no erythrocyte lysis was observed after incubation with preformed IAPP fibrils. In contrast, monomeric alpha chain of C4BP had significantly reduced activity. Further, addition of monomeric IAPP to a rat insulinoma cell line (INS-1) resulted in decreased cell viability, which was restored in the presence of physiological concentrations of C4BP. Accordingly, addition of C4BP rescued the ability of INS-1 cells and isolated rat islets to respond to glucose stimulation with insulin secretion, which was impaired in the presence of IAPP alone. C4BP was internalized together with IAPP into INS-1 cells and therefore we aimed to study its effect on gene expression. Pathway analyses of mRNA expression microarray data indicated that cells exposed to C4BP and IAPP in comparison to IAPP alone increased expression of genes involved in cholesterol synthesis. Depletion of cholesterol through methyl-Î²-cyclodextrin or cholesterol oxidase abolished the protective effect of C4BP on IAPP cytotoxicity of INS-1 cells. Also, inhibition of phosphoinositide 3-kinase but not NF-ÎºB had a similar effect. Taken together, one of the mechanisms by which C4BP protects beta-cells from IAPP cytotoxicity is by enhancing cholesterol synthesis. The INS-1 cells were grown as 5 separate clones for 10 passages before plating in a 12-well plate (Nunc) at 100.000 cells per well and grown in complete RPMI 1640 medium to 70% confluency for approximately 48 h. The cells were then challenged by adding 77 Î¼M monomeric IAPP alone or together with C4BP (0.6 Î¼M). DMSO (1%) used as solvent for IAPP as well as C4BP (0.6 Î¼M) alone were used as controls. RNA was extracted after 10h incubation and analysis carried out using Rat Gene 2.0 array chip (Affymetrix).

Dataset Information

TMPyP Inhibits Amyloid-? Aggregation and Alleviates Amyloid-Induced Cytotoxicity.

Publications

TMPyP Inhibits Amyloid-β Aggregation and Alleviates Amyloid-Induced Cytotoxicity.

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