Interaction of Aβ(25–35) fibrillation products with mitochondria: Effect of small‐molecule natural products

Abstract

The 25-35 fragment of the amyloid β (Aβ) peptide is a naturally occurring proteolytic by-product that retains the pathophysiology of its larger parent molecule, whose deposition has been shown to involve mitochondrial dysfunction. Hence, disruption of Aβ(25-35) aggregates could afford an effective remedial strategy for Alzheimer's disease (AD). In the present study, the effect of a number of selected small-molecule natural products (polyphenols: resveratrol, quercetin, biochanin A, and indoles: indole-3-acetic acid, indole-3-carbinol (I3C)) on Aβ(25-35) fibrillogenesis was explored under physiological conditions, and interaction of the resulting structures with rat brain mitochondria was investigated. Several techniques, including fluorescence, circular dichroism, and transmission electron microscopy were utilized to characterize the aggregation products, and possible mitochondrial membrane permeabilization was determined following release of marker enzymes. Results demonstrate the capacity of Aβ(25-35) fibrils to damage mitochondria and suggest how small molecules may afford protection. While I3C appeared more effective in inhibiting the fibrillation process, all natural products behaved similarly in destabilizing preformed aggregates. It is concluded that elucidation of such protection may provide important insights into the development of preventive and therapeutic agents for AD.

Inhibition of amyloid fibrillation and cytotoxicity of lysozyme fibrillation products by polyphenols

“…These results indicate that both polyphenols delay the onset of HEWL secondary structural conversion from a partially unfolded to ␤ structure, suggesting that they probably bind to amyloidogenic structures formed during early stages of fibrillation, and not to the monomers, in accord with earlier reports on studies involving a number of proteins/peptides [22,27,30,32,70]. Our observation that both polyphenols prolonged the lag time of HEWL fibrillation support the notion that the polyphenols interfere with the initial steps of HEWL amyloid formation (Table 1).…”

“…In this regard, numerous reports have demonstrated the effectiveness of some of the naturally occurring small molecules, and specially certain natural polyphenols, on prevention of protein aggregation and their associated cytotoxicity [24][25][26][27][28][29][30][31]. Recently, we too, have reported on inhibition of fibrillation as well as destabilization of preformed fibrils of A␤ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), using a range of small molecules, including polyphenols [32]. Based on structural similarities, a structure-function relationship study has suggested that the presence of at least two phenolic rings with two to six atom linkers, along with a minimum number of three OH groups on the aromatic rings, are essential for efficient polyphenol inhibition [22].…”

Docking Studies and Biological Evaluation of a Potential β-Secretase Inhibitor of 3-Hydroxyhericenone F from Hericium erinaceus

“…The sections on the grids were post-stained for 2 min with 1% UA, and for 6 min with 1% lead citrate by the addition of single drops of the staining solution at room temperature. The sections were rinsed in deionized water, dried and finally observed using a H7650 electron microscope (Hitachi, Tokyo, Japan), as described in previous studies (Ghobeh et al, 2014). …”

Mitochondria as a Target for Safety and Toxicity Evaluation of Nutraceuticals

“…Treatment of airway epithelial cells with quercetin during hMPV infection significantly reduced cellular oxidative damage, inflammatory mediator secretion, and viral replication, supporting the use of dietary antioxidants such as quercetin as an effective treatment approach for modulating hMPV-induced lung oxidative damage and inflammation (Komaravelli et al, 2015). Quercetin and other polyphenols, such as resveratrol, were used in a study to protect brain mitochondria from amyloid fragment fibrillogenesis (Ghobeh et al, 2014). Using rat hippocampal cultures, some authors have already been capable of delivering encapsulated quercetin, protecting neuronal cultures from oxidative stress, and hypothesizing its use against AD or other neurodegenerative disorders (Nday et al, 2015).…”