A catalytic antioxidant for limiting amyloid-beta peptide aggregation and reactive oxygen species generation

Gomes, Luiza M. F.; Mahammed, Atif; Prosser, Kathleen E.; Smith, Jason Scott; Silverman, Michael; Walsby, Charles J.; Gross, Zeev; Storr, Tim

doi:10.1039/c8sc04660c

Cited by 53 publications

(44 citation statements)

References 134 publications

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“…At each time point (3, 6, 11, and 24 h) a 30 µL aliquot was removed from the stock incubation solution for each treatment and kept at −80 • C until further analysis. An increase in high MW aggregates over time was observed for Aβ 1−42 alone (Lane 1, Figure 3), with a significant decrease in soluble Aβ species at 24 h, as expected based on prior results (Jones et al, 2015;Gomes et al, 2019). The Ru-N derivatives do not significantly affect aggregation at the 3 h timepoint.…”

Section: Influence Of Ru-n Series On Aβ Aggregationsupporting

confidence: 84%

Modification of Aβ Peptide Aggregation via Covalent Binding of a Series of Ru(III) Complexes

et al. 2019

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Alzheimer's disease (AD) is the most common form of dementia, leading to loss of cognition, and eventually death. The disease is characterized by the formation of extracellular aggregates of the amyloid-beta (Aβ) peptide and neurofibrillary tangles of tau protein inside cells, and oxidative stress. In this study, we investigate a series of Ru(III) complexes (Ru-N) derived from NAMI-A in which the imidazole ligand has been substituted for pyridine derivatives, as potential therapeutics for AD. The ability of the RuN series to bind to Aβ was evaluated by NMR and ESI-MS, and their influence on the Aβ peptide aggregation process was investigated via electrophoresis gel/western blot, TEM, turbidity, and Bradford assays. The complexes were shown to bind covalently to the Aβ peptide, likely via a His residue. Upon binding, the complexes promote the formation of soluble high molecular weight aggregates, in comparison to peptide precipitation for peptide alone. In addition, TEM analysis supports both amorphous and fibrillar aggregate morphology for RuN treatments, while only large amorphous aggregates are observed for peptide alone. Overall, our results show that the RuN complexes modulate Aβ peptide aggregation, however, the change in the size of the pyridine ligand does not substantially alter the Aβ aggregation process.

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Section: Influence Of Ru-n Series On Aβ Aggregationsupporting

confidence: 84%

Modification of Aβ Peptide Aggregation via Covalent Binding of a Series of Ru(III) Complexes

et al. 2019

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“…Previous studies have demonstrated that variations in cell toxicity are correlated with the Ab 40 aggregation state, meaning that they could be subject to potential modulation (i.e., enhanced or retarded toxicity) by porphyrinoid additives. [30][31][32] MMn appears particularly effective in this regard.…”

Section: Cellular Assays and Stability Studiesmentioning

confidence: 98%

“…The interaction of hemin and other water-soluble phthalocyanines, corroles, and porphyrins with Ab has been noted. [29][30][31][32] We thus envisaged that coupling the Ab-recognition properties of metalloporphyrins with the biological activity of metallotexaphyrins would allow for MRI recognition of Ab species with attendant utility as a potential metalloantioxidant therapeutic ( Figure 2). As detailed further below, we have found that metallotexaphyrins, in particular MMn, interact with amyloid constructs, as inferred from ultraviolet-visible (UV-vis), fluorescence, and circular dichroism (CD) spectroscopies, as well as MRI studies.…”

Section: Introductionmentioning

confidence: 99%

Metallotexaphyrins as MRI-Active Catalytic Antioxidants for Neurodegenerative Disease: A Study on Alzheimer’s Disease

Brewster

Harvey

Zafar

et al. 2020

Chem

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Sessler et al. have studied manganese(II) texaphyrin as a catalytic metalloantioxidant theranostic agent for the detection of Ab aggregates. A series of in vitro and in vivo analyses allowed for the inference that metallotexaphyrins could be used for MRI-based detection of Ab biomarkers. In vitro and cellularbased assays coupled with mechanistic analysis demonstrated an efficacious protective effect against oxidative and nitrative damage. The present results could thus guide future efforts in developing new theranostic modalities for use in neurodegenerative disease.

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“…Several studies indicated that the antioxidant defense system in some elderly people lost its ability to neutralize the oxidative substance. In the early AD stage, the oxidative stress could initiate the Aβ aggregation and tau protein hyperphosphorylation (Gomes et al, 2018). Many evidences have proved that the antioxidants could attenuate the AD syndrome, and prevent the disease progression (Gomes et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…In the early AD stage, the oxidative stress could initiate the Aβ aggregation and tau protein hyperphosphorylation (Gomes et al, 2018). Many evidences have proved that the antioxidants could attenuate the AD syndrome, and prevent the disease progression (Gomes et al, 2018). Thus, drugs with specifically antioxidant activity might be useful for either the prevention or the treatment of AD.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological activity evaluation of BACE1 inhibitors with antioxidant activity

He-min

Fan

et al. 2019

Drug Development Research

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The proteolytic enzyme β‐secretase (BACE1) plays a central role in the synthesis of the pathogenic β‐amyloid peptides (Aβ) in Alzheimer's disease (AD), antioxidants could attenuate the AD syndrome and prevent the disease progression. In this study, BACE1 inhibitors (D1–D18) with free radical‐scavenging activities were synthesized by molecular hybridization of 2‐aminopyridine with natural antioxidants. The biological activity evaluation showed that D1 had obvious inhibitory activity against BACE1, and strong antioxidant activity in 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) and 2,2′‐azinobis‐(3‐ethylbenzthiazoline‐6‐sulphonate) (ABTS+•) assay, which could be used as a lead compound for further study.

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A catalytic antioxidant for limiting amyloid-beta peptide aggregation and reactive oxygen species generation

Abstract: An Fe corrole is shown to bind to the amyloid-beta peptide and limit reactive oxygen species generation and peptide aggregation of relevance to Alzheimer's disease.

Cited by 53 publications

References 134 publications

Modification of Aβ Peptide Aggregation via Covalent Binding of a Series of Ru(III) Complexes

Modification of Aβ Peptide Aggregation via Covalent Binding of a Series of Ru(III) Complexes

Metallotexaphyrins as MRI-Active Catalytic Antioxidants for Neurodegenerative Disease: A Study on Alzheimer’s Disease

Design, synthesis, and biological activity evaluation of BACE1 inhibitors with antioxidant activity

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