Abstract: Amyloid-β (Aβ) aggregation is a recognized key process in the pathogenesis of Alzheimer's disease (AD). Misfolded Aβ peptides self-assemble into higher-order oligomers that compromise membrane integrity, leading to synaptic degeneration and neuronal cell death. The main aim of this study was to explore whether small-molecule compounds and black tea extract can protect phospholipid membranes from disruption by Aβ aggregates. We first established a robust protocol for aggregating Aβ42 peptides into a range of oligomers that efficiently permeabilized small unilamellar liposomes. Next, 15 natural plant polyphenolic compounds, 8 N′-benzylidene-benzohydrazide (NBB) compounds and black tea extract were assessed for their ability to…antagonize liposome permeabilization by the Aβ42 oligomers. Our data indicates that black tea extract, the flavones apigenin and baicalein, and the stilbene nordihydroguaiaretic acid (NDGA) are indeed potent inhibitors. Taking into consideration the results of all the small-molecule polyphenols and NBB compounds, it can be proposed that a dihydroxyphenyl ring structure, alone or as part of a flavone scaffold, is particularly effective for protection against membrane damage by the Aβ42 oligomers. Given the critical role of membrane perforation in the neurodegenerative cascade, these conclusions may guide the design and development of novel therapeutic drugs in AD.
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Keywords: Alzheimer's disease, amyloid-β, black tea, liposomes, N′-benzylidene-benzohydrazide, oligomers, polyphenols
Abstract: Background: Synucleinopathies such as Parkinson's disease are characterized by the deposition of aggregated α-synuclein in affected brain areas. As genes involved in mitochondrial function, mitochondrial toxins, and age-related mitochondrial impairment have been implicated in Parkinson's disease pathogenesis, an increase in reactive oxygen species resulting from mitochondrial dysfunction has been speculated to induce α-synuclein aggregation. In vitro, pore-forming, SDS-resistant α-synuclein oligomers are formed in presence of ferric iron and may represent an important toxic particle species. Methodology/Principal findings: We investigated the interplay of reactive oxygen species, antioxidants and iron oxidation state in regard to α-synuclein aggregation using confocal single particle fluorescence…spectroscopy, Phenanthroline spectrometry and thiobarbituric acid reactive substances assay. We found that the formation of α-synuclein oligomers in presence of Fe3+ is due to a direct interaction. In contrast, oxidizing agents and hydroxyl radicals generated in the Fenton reaction did not directly affect α-synuclein oligomerization. However, reactive oxygen species could enhance aggregation via oxidation of ferrous to ferric iron when iron ions were present. Conclusions/Significance: Our data thus indicate that oxidative stress affects α-synuclein aggregation via oxidation of iron to the ferric state. This provides a new perspective on the role of mitochondrial toxins and mitochondrial dysfunction in the pathogenesis of Parkinson's disease.
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Keywords: Parkinson's disease, α-synuclein, iron, oxidative stress, protein aggregation, pesticides