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Inhibition of Beta-Amyloid Fibrillation by Luminescent Iridium(III) Complex Probes.

Lu L, Zhong HJ, Wang M, Ho SL, Li HW, Leung CH, Ma DL - Sci Rep (2015)

Bottom Line: We report herein the application of kinetically inert luminescent iridium(III) complexes as dual inhibitors and probes of beta-amyloid fibrillogenesis.These iridium(III) complexes inhibited Aβ1-40 peptide aggregation in vitro, and protected against Aβ-induced cytotoxicity in neuronal cells.Furthermore, the complexes differentiated between the aggregated and unaggregated forms of Aβ1-40 peptide on the basis of their emission response.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.

ABSTRACT
We report herein the application of kinetically inert luminescent iridium(III) complexes as dual inhibitors and probes of beta-amyloid fibrillogenesis. These iridium(III) complexes inhibited Aβ1-40 peptide aggregation in vitro, and protected against Aβ-induced cytotoxicity in neuronal cells. Furthermore, the complexes differentiated between the aggregated and unaggregated forms of Aβ1-40 peptide on the basis of their emission response.

No MeSH data available.


Related in: MedlinePlus

Inhibition of seed-mediated Aβ1–40 fibril growth by Ir(III) complexes.TIRFM images of Aβ1–40 fibrils grown in the (a) absence and presence of (b) 13, (c) 14 after incubation at 37 °C for 1 h. The scale bar for TIRFM is 20 μm.
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f2: Inhibition of seed-mediated Aβ1–40 fibril growth by Ir(III) complexes.TIRFM images of Aβ1–40 fibrils grown in the (a) absence and presence of (b) 13, (c) 14 after incubation at 37 °C for 1 h. The scale bar for TIRFM is 20 μm.

Mentions: Complexes 12–14 were investigated for their ability to inhibit the fibrillogenesis of Aβ1–40. Given that these complexes could detect Aβ1–40 fibrils over Aβ1–40 monomers, the kinetics of Aβ1–40 aggregation in the presence of the complexes could be monitored without the need for an external labeling agent. The results revealed typical sigmoidal growth curves in seed-mediated Aβ fibrillation when Aβ1–40 monomers was incubated with ThT or 12–14 (Figure S2a and S2b). However, fibrillogenesis was partial retarded by 13 and completely inhibited by 14, indicating that these two complexes were able to inhibit Aβ1–40 peptide aggregation. As both 13 and 14 contain the phenol-imidazo-phen N^N ligand, the effect of that ligand alone on Aβ1–40 peptide aggregation was investigated. The results showed that the presence of the N^N ligand alone had no inhibitory effect on Aβ1–40 peptide aggregation, highlighting the importance of the iridium(III) metal center in maintaining the octahedral structure of the active complexes (Figure S2c). Moreover, total internal reflection fluorescence microscopy (TIRFM) with laser excitation was used to observe the ThT-labelled fibrils with high sensitivity. In the absence of Ir(III) complexes, the fluorescence images of the Aβ1–40 peptides incubated by the seed-mediated method showed dense spots, corresponding to newly genereted Aβ1–40 fibrils (Fig. 2a). In contrast, these spots partially or completely disappeared when the samples were treated with 13 (Fig. 2b) or 14 (Fig. 2c), indicating that 13 and 14 could partially or completely inhibit the fibrillogenesis of amyloid peptides, respectively. Transmission electron microscopy (TEM) images further confirmed the ability of the Ir(III) complexes to inhibit seed-mediated Aβ aggregation. In the control experiment (Fig. 3a), Aβ1–40 grewinto thick, dense and long hair-like fibrils. However, when the sample was incubated with 13, the TEM image showed short flake-like fibris (Fig. 3b), indicating that 13 was able to partially inhibit the Aβ1–40 aggregation. Furthermore, incubation of the sample with 14 resulted in the complete absence of elongated fibrils, and only the preformed fibril seeds were observed (Fig. 3c), indicating the complete inhibition amyloid fibrillogenesis by 14. Moreover, the fibrillogenesis kinetics of Aβ1–40 in the presence of various concentrations of 14 showed that the inhibition of Aβ1–40 aggregation by 14 was concentration-dependent (Figure S3). At 50 μM of 14, the inhibition of 25 μM of Aβ1–40 peptides was nearly completely inhibited.


Inhibition of Beta-Amyloid Fibrillation by Luminescent Iridium(III) Complex Probes.

Lu L, Zhong HJ, Wang M, Ho SL, Li HW, Leung CH, Ma DL - Sci Rep (2015)

Inhibition of seed-mediated Aβ1–40 fibril growth by Ir(III) complexes.TIRFM images of Aβ1–40 fibrils grown in the (a) absence and presence of (b) 13, (c) 14 after incubation at 37 °C for 1 h. The scale bar for TIRFM is 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588514&req=5

f2: Inhibition of seed-mediated Aβ1–40 fibril growth by Ir(III) complexes.TIRFM images of Aβ1–40 fibrils grown in the (a) absence and presence of (b) 13, (c) 14 after incubation at 37 °C for 1 h. The scale bar for TIRFM is 20 μm.
Mentions: Complexes 12–14 were investigated for their ability to inhibit the fibrillogenesis of Aβ1–40. Given that these complexes could detect Aβ1–40 fibrils over Aβ1–40 monomers, the kinetics of Aβ1–40 aggregation in the presence of the complexes could be monitored without the need for an external labeling agent. The results revealed typical sigmoidal growth curves in seed-mediated Aβ fibrillation when Aβ1–40 monomers was incubated with ThT or 12–14 (Figure S2a and S2b). However, fibrillogenesis was partial retarded by 13 and completely inhibited by 14, indicating that these two complexes were able to inhibit Aβ1–40 peptide aggregation. As both 13 and 14 contain the phenol-imidazo-phen N^N ligand, the effect of that ligand alone on Aβ1–40 peptide aggregation was investigated. The results showed that the presence of the N^N ligand alone had no inhibitory effect on Aβ1–40 peptide aggregation, highlighting the importance of the iridium(III) metal center in maintaining the octahedral structure of the active complexes (Figure S2c). Moreover, total internal reflection fluorescence microscopy (TIRFM) with laser excitation was used to observe the ThT-labelled fibrils with high sensitivity. In the absence of Ir(III) complexes, the fluorescence images of the Aβ1–40 peptides incubated by the seed-mediated method showed dense spots, corresponding to newly genereted Aβ1–40 fibrils (Fig. 2a). In contrast, these spots partially or completely disappeared when the samples were treated with 13 (Fig. 2b) or 14 (Fig. 2c), indicating that 13 and 14 could partially or completely inhibit the fibrillogenesis of amyloid peptides, respectively. Transmission electron microscopy (TEM) images further confirmed the ability of the Ir(III) complexes to inhibit seed-mediated Aβ aggregation. In the control experiment (Fig. 3a), Aβ1–40 grewinto thick, dense and long hair-like fibrils. However, when the sample was incubated with 13, the TEM image showed short flake-like fibris (Fig. 3b), indicating that 13 was able to partially inhibit the Aβ1–40 aggregation. Furthermore, incubation of the sample with 14 resulted in the complete absence of elongated fibrils, and only the preformed fibril seeds were observed (Fig. 3c), indicating the complete inhibition amyloid fibrillogenesis by 14. Moreover, the fibrillogenesis kinetics of Aβ1–40 in the presence of various concentrations of 14 showed that the inhibition of Aβ1–40 aggregation by 14 was concentration-dependent (Figure S3). At 50 μM of 14, the inhibition of 25 μM of Aβ1–40 peptides was nearly completely inhibited.

Bottom Line: We report herein the application of kinetically inert luminescent iridium(III) complexes as dual inhibitors and probes of beta-amyloid fibrillogenesis.These iridium(III) complexes inhibited Aβ1-40 peptide aggregation in vitro, and protected against Aβ-induced cytotoxicity in neuronal cells.Furthermore, the complexes differentiated between the aggregated and unaggregated forms of Aβ1-40 peptide on the basis of their emission response.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.

ABSTRACT
We report herein the application of kinetically inert luminescent iridium(III) complexes as dual inhibitors and probes of beta-amyloid fibrillogenesis. These iridium(III) complexes inhibited Aβ1-40 peptide aggregation in vitro, and protected against Aβ-induced cytotoxicity in neuronal cells. Furthermore, the complexes differentiated between the aggregated and unaggregated forms of Aβ1-40 peptide on the basis of their emission response.

No MeSH data available.


Related in: MedlinePlus