Insight into the molecular mechanism underlying the inhibition of α-synuclein aggregation by hydroxytyrosol

Palazzi, Luana; Leri, Manuela; Cesaro, Samuele; Stefani, Massimo; Bucciantini, Monica; Laureto, Patrizia Polverino de

doi:10.1016/j.bcp.2019.113722

Cited by 29 publications

(48 citation statements)

References 75 publications

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“…Six-month HT administration to three-month-old female transgenic APP/PS1 mice at 5 mg/kg/day improved the electroencephalographic activity and cognitive function and reduced mitochondrial oxidative stress and neuroinflammation [140]. Moreover, HT was shown to dose-dependently inhibit toxicity of α-synuclein aggregation in PD [141] and HT and OLE improved spatial working memory and energetic metabolism in the brain of aged mice [142]. Notably, HT efficiently neutralizes free radicals and protects biomolecules from ROS-induced oxidative damage.…”

Section: Redox Homeostasis and The Inflammatory Responsementioning

confidence: 97%

Healthy Effects of Plant Polyphenols: Molecular Mechanisms

Leri

Scuto

Ontario

et al. 2020

IJMS

Self Cite

331

213

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The increasing extension in life expectancy of human beings in developed countries is accompanied by a progressively greater rate of degenerative diseases associated with lifestyle and aging, most of which are still waiting for effective, not merely symptomatic, therapies. Accordingly, at present, the recommendations aimed at reducing the prevalence of these conditions in the population are limited to a safer lifestyle including physical/mental exercise, a reduced caloric intake, and a proper diet in a convivial environment. The claimed health benefits of the Mediterranean and Asian diets have been confirmed in many clinical trials and epidemiological surveys. These diets are characterized by several features, including low meat consumption, the intake of oils instead of fats as lipid sources, moderate amounts of red wine, and significant amounts of fresh fruit and vegetables. In particular, the latter have attracted popular and scientific attention for their content, though in reduced amounts, of a number of molecules increasingly investigated for their healthy properties. Among the latter, plant polyphenols have raised remarkable interest in the scientific community; in fact, several clinical trials have confirmed that many health benefits of the Mediterranean/Asian diets can be traced back to the presence of significant amounts of these molecules, even though, in some cases, contradictory results have been reported, which highlights the need for further investigation. In light of the results of these trials, recent research has sought to provide information on the biochemical, molecular, epigenetic, and cell biology modifications by plant polyphenols in cell, organismal, animal, and human models of cancer, metabolic, and neurodegenerative pathologies, notably Alzheimer’s and Parkinson disease. The findings reported in the last decade are starting to help to decipher the complex relations between plant polyphenols and cell homeostatic systems including metabolic and redox equilibrium, proteostasis, and the inflammatory response, establishing an increasingly solid molecular basis for the healthy effects of these molecules. Taken together, the data currently available, though still incomplete, are providing a rationale for the possible use of natural polyphenols, or their molecular scaffolds, as nutraceuticals to contrast aging and to combat many associated pathologies.

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Section: Redox Homeostasis and The Inflammatory Responsementioning

confidence: 97%

Healthy Effects of Plant Polyphenols: Molecular Mechanisms

Leri

Scuto

Ontario

et al. 2020

IJMS

Self Cite

331

213

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“…In the present paper, we focus on health effects of hydroxytyrosol (HT; Figure 1B) and oleuropein aglycone (OLE; Figure 1A) as neuroprotective agents against PD in the light of recent studies indicating that OLE and HT can be beneficial against PD by stabilizing the monomeric state of α-synuclein, thus, favouring the growth of aggregates devoid of toxicity [36,37]. Furthermore, previous studies have shown that these molecules are strongly protective against neurodegeneration in different transgenic models of Aβ deposition [38][39][40].…”

Section: Introductionmentioning

confidence: 99%

Healthspan Maintenance and Prevention of Parkinson’s-like Phenotypes with Hydroxytyrosol and Oleuropein Aglycone in C. elegans

Brunetti

Rosa

Scuto

et al. 2020

IJMS

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125

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Numerous studies highlighted the beneficial effects of the Mediterranean diet (MD) in maintaining health, especially during ageing. Even neurodegeneration, which is part of the natural ageing process, as well as the foundation of ageing-related neurodegenerative disorders like Alzheimer’s and Parkinson’s disease (PD), was successfully targeted by MD. In this regard, olive oil and its polyphenolic constituents have received increasing attention in the last years. Thus, this study focuses on two main olive oil polyphenols, hydroxytyrosol (HT) and oleuropein aglycone (OLE), and their effects on ageing symptoms with special attention to PD. In order to avoid long-lasting, expensive, and ethically controversial experiments, the established invertebrate model organism Caenorhabditis elegans was used to test HT and OLE treatments. Interestingly, both polyphenols were able to increase the survival after heat stress, but only HT could prolong the lifespan in unstressed conditions. Furthermore, in aged worms, HT and OLE caused improvements of locomotive behavior and the attenuation of autofluorescence as a marker for ageing. In addition, by using three different C. elegans PD models, HT and OLE were shown i) to enhance locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure, ii) to reduce α-synuclein accumulation in muscles cells, and iii) to prevent neurodegeneration in α-synuclein-containing dopaminergic neurons. Hormesis, antioxidative capacities and an activity-boost of the proteasome & phase II detoxifying enzymes are discussed as potential underlying causes for these beneficial effects. Further biological and medical trials are indicated to assess the full potential of HT and OLE and to uncover their mode of action.

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“…Recently, several studies have suggested that natural phenolic compounds can interfere with the amyloid aggregation process both by affecting the amyloid intermediate formation and promoting the aggregation cascade towards nontoxic species [58,59]. In particular, the main phenolic compounds of extra-virgin olive oil, i.e., oleuropein aglycone (OleA) and its main metabolite, hydroxytyrosol (3,4-dihydroxyphenylethanol (HT), aside from their biological and pharmacological properties, have been shown to affect the amyloid aggregation process in different model proteins in vitro [12,[15][16][17][18][19][20][21]60]. Because only little information is available for HT compared to OleA, in this study, we tested the molecular effect of HT in the amyloid aggregation process of human insulin.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, HT has been shown to affect the amyloid aggregation process in hen egg white lysozyme, Aβ 1-42 , Amylin, Tau protein and α-synuclein [15][16][17][18]20,21]. In particular, HT has been suggested to interact with these amyloidogenic proteins and affect amyloid intermediate formation as well as promote the formation of off-pathway species unable to induce cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…HT ( Figure 1) is also highly concentrated in red wine and can be endogenously produced via dopamine metabolism [10,11]. Recently, OleA and HT have been shown to affect the amyloid aggregation process in different model proteins in vitro although the molecular mechanisms have been poorly characterized [12][13][14][15][16][17][18][19][20][21]. Because only little information is available for HT compared to OleA and considering that HT is one of the main metabolites of OleA, further studies could be useful for a better understanding of the antiamyloidogenic properties of this compound.…”

Section: Introductionmentioning

confidence: 99%

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Hydroxytyrosol Inhibits Protein Oligomerization and Amyloid Aggregation in Human Insulin

Sirangelo

Borriello

Vilasi

2020

IJMS

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Hydroxytyrosol (HT), one of the main phenolic components of olive oil, has attracted considerable interest for its biological properties, including a remarkable antioxidant and anti-inflammatory power and, recently, for its ability to interfere with the amyloid aggregation underlying several human diseases. We report here a broad biophysical approach and cell biology techniques that allowed us to characterize the molecular mechanisms by which HT affects insulin amyloid aggregation and the related cytotoxicity. Our data show that HT is able to fully inhibit insulin amyloid aggregation and this property seems to be ascribed to the stabilization of the insulin monomeric state. Moreover, HT completely reverses the toxic effect produced by amyloid insulin aggregates in neuroblastoma cell lines by fully inhibiting the production of toxic amyloid species. These findings suggest that the beneficial effects of olive oil polyphenols, including HT, may arise from multifunctional activities and suggest possible a application of this natural compound in the prevention or treatment of amyloid-associated diseases.

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Insight into the molecular mechanism underlying the inhibition of α-synuclein aggregation by hydroxytyrosol

Cited by 29 publications

References 75 publications

Healthy Effects of Plant Polyphenols: Molecular Mechanisms

Healthy Effects of Plant Polyphenols: Molecular Mechanisms

Healthspan Maintenance and Prevention of Parkinson’s-like Phenotypes with Hydroxytyrosol and Oleuropein Aglycone in C. elegans

Hydroxytyrosol Inhibits Protein Oligomerization and Amyloid Aggregation in Human Insulin

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