The accumulation and deposition of fibrillar aggregates of α-synuclein (α-syn) into Lewy bodies are the major hallmarks of Parkinson's disease (PD) for which there is no cure yet. Disrupting preformed α-syn fibrils is considered one of the rational therapeutic strategies to combat PD. Experimental studies reported that epigallocatechin gallate (EGCG), a polyphenol extracted from green tea, can disrupt α-syn fibrils into benign amorphous aggregates. However, the molecular mechanism of action is poorly understood. Herein, we performed molecular dynamics simulations on a newly released Greek-key-like α-syn fibril with or without EGCG to investigate the influence of EGCG on α-syn fibril. Our simulations show that EGCG disrupts the local β-sheet structure, E46-K80 salt-bridge crucial for the stabilization of the Greek-key-like structure, and hydrophobic interactions stabilizing the inter-protofibril interface and destabilizes the global structure of the α-syn fibril. Interaction analyses reveal that hydrophobic and hydrogen-bonding interactions between EGCG and α-syn fibrils play important roles in the destabilization of the fibril. We find that the disruption of the E46-K80 salt-bridge closely correlates with the formation of hydrogen-bonds (H-bonds) between EGCG and E46/K80. Our results provide mechanistic insights into the disruption modes of α-syn fibril by EGCG, which may pave the way for designing drug candidates targeting α-syn fibrillization to treat PD.

Epigallocatechin Gallate Destabilizes α-Synuclein Fibril by Disrupting the E46–K80 Salt-Bridge and Inter-protofibril Interface

Spectroscopic, molecular docking and molecular dynamic simulation studies on the complexes of β-lactoglobulin, safranal and oleuropein

In the central nervous system (CNS), extra virgin olive oil (EVOO) produces interesting effects against neurodegenerative disorders including Alzheimer's disease (AD). The valuable properties of EVOO are largely ascribed to oleuropein aglycone (OA), its most abundant phenolic constituent. In particular, it has been demonstrated that in AD, OA produces strong neuroprotective effects being able to reduce amyloid β (Aβ) aggregates, thereby diminishing the related cytotoxicity and inflammation. OA prevents Aβ aggregation, but more importantly OA was able to disrupt the preformed Aβ fibrils. Herein, we describe a comprehensive computational investigation of the mechanism of action of OA as an Aβ fibril disruptor at the molecular level. We employed extensive molecular docking calculations and long-time molecular dynamics simulation for mimicking the system of OA/Aβ fibrils. The results showed that OA is able to move in depth within the Aβ fibrils targeting a key motif in Aβ peptide, known to be relevant for stabilizing the assembled fibrils. OA causes a structural instability of preformed Aβ fibrils, determining the effective Aβ fibril disaggregation. Accordingly, this study highlighted the role of OA as a potent anti-amyloidogenic drug. On the other hand, our work has relevant implications for rationally designing potent multifunctional compounds acting as disease modifying anti-Alzheimer's drugs for the development of innovative anti-AD therapeutics.

Amyloid β fibril disruption by oleuropein aglycone: long-time molecular dynamics simulation to gain insight into the mechanism of action of this polyphenol from extra virgin olive oil

Neurodegenerative diseases are driven by several mechanisms such as inflammation, abnormal protein aggregation, excitotoxicity, mitochondrial dysfunction and oxidative stress. So far, no therapeutic strategies are available for neurodegenerative diseases and in recent years the research is focusing on bioactive molecules present in food. In particular, extra-virgin olive oil (EVOO) phenols have been associated to neuroprotection. In this study, we investigated the potential antioxidant and neuroprotective activity of two different EVOO extracts obtained from Quercetano cultivar trees grown in two different areas (plain and hill) of the Tuscany region (Italy). The different geographical origin of the orchards influenced phenol composition. Plain extract presented a higher content of phenyl ethyl alcohols, cinnammic acids, oleacein, oleocanthal and flavones; meanwhile, hill extract was richer in lignans. Hill extract was more effective in protecting differentiated SH-SY5Y cells from peroxide stress thanks to a marked upregulation of the antioxidant enzymes heme oxygenase 1, NADPH quinone oxidoreductase 1, thioredoxin Reductase 1 and glutathione reductase. Proteomic analysis revealed that hill extract plays a role in the regulation of proteins involved in neuronal plasticity and activation of neurotrophic factors such as BDNF. In conclusion, these data demonstrate that EVOOs can have important neuroprotective activities, but these effects are strictly related to their specific phenol composition.

https://www.mdpi.com/2076-3921/10/3/421/pdf

Antioxidant and Neuroprotective Activity of Extra Virgin Olive Oil Extracts Obtained from Quercetano Cultivar Trees Grown in Different Areas of the Tuscany Region (Italy).

Neurological disorders are increasing at a faster pace due to oxidative stress, protein aggregation, excitotoxicity, and neuroinflammation. It is reported that the Mediterranean diet including olives as a major dietary component prevents and ameliorates neurological anomalies. Oleuropein is the major bioactive component in different parts of the Olive (Olea europaea L.) tree. Several mechanisms have been reported for the neuroprotective role of oleuropein including induction of apoptosis and autophagy, enhancing the antioxidant pool of the cerebral region, decreasing the unnecessary release of proinflammatory cytokines and chemokines by deactivating the microglia cells and astrocytes thus preventing the occurrence of neuroinflammation. Regular intake of oleuropein seems to be correlated with decreased risks of neural disorders including Alzheimer's, Parkinson's, strokes, depression, anxiety, epilepsy, and others. This review majorly discusses the chemistry, biosynthesis, and metabolism of oleuropein along with an updated vision of its neuroprotective role in counteracting the acute and chronic neurodegenerative and neuropsychiatric disorders. Moreover, mechanisms by which oleuropein may prevent neurodegeneration are reviewed. PRACTICAL APPLICATION: Neurological disorders are negatively affecting the health and life quality of individuals around the globe. Although various medicinal solutions are available to tackle such ailments, none has proven to fully cure and being deprived of side effects. In this respect, the prevention of such disorders using natural remedies may be an effective strategy to overcome the incidence of the increasing cases. Furthermore, the natural compounds provide a safer alternative to pharmaceutical drugs. Hence, oleuropein from olive tree products is found to be efficacious against neurological disorders. This review provides an updated insight on the positive effects of oleuropein against neurodegenerative and neuropsychiatric disorders. The diet practitioners and nutraceutical companies may benefit from the provided information to design and develop strategies to improve the mental health of suffering individuals.

Neuroprotective effects of oleuropein: Recent developments and contemporary research.

Parkinson’s disease (PD) is considered to be the second most common progressive neurodegenerative brain disorder after Alzheimer’s disease, which is caused by misfolding and aggregation of Alpha-sy...

Computational investigation on the effect of Oleuropein aglycone on the α-synuclein aggregation.

Alzheimer’s disease (AD) is the most common progressive neurodegenerative brain disorder. It is characterized by the presence of extracellular aggregated fibrillary form of amyloid beta (Aβ) peptid...

Priyanka Borah

Papers

Computational investigation on the effect of Oleuropein aglycone on the α-synuclein aggregation.

Effect of CTerm of human albumin on the aggregation propensity of Aβ1-42 peptide: a potential of mean force study.