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Natural Inhibitors of Amyloid Aggregation
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Natural Inhibitors of Amyloid Aggregation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (20 December 2019) | Viewed by 31695

Special Issue Editors

Prof. Dr. Paolo Tortora

E-Mail Website
Guest Editor
Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy
Interests: polyglutamine proteins; amyloid diseases; antiamyloid compounds; nanobiotechnology; Caenorhabditis elegans
Dr. Francesco A. Aprile

E-Mail Website
Guest Editor
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
Interests: dementia; Alzheimer’s disease; Parkinson’s disease; neurodegeneration; protein aggregation; molecular chaperones; antibodies; protein therapeutics; protein design; biophysiscs

Special Issue Information

Dear Colleagues,

The formation of fibrillar aggregates, called amyloids, of normally soluble proteins in the nervous system is a pathological event strongly linked with selective neuronal death. This mechanism underlies the onset and progression of several forms of dementia and motor neuron diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.

Amyloid aggregation is an extremely intricate process that involves several events and the formation of transient and highly toxic species, called oligomers. The intrinsic instability of oligomers represents a major challenge in the field, which has hindered the development of therapeutic strategies. Nevertheless, as a result of several recent advances, current drug discovery approches aimed at inhibiting amyloid aggregation and, specifically, the formation of oligomers are under development and show promising results. Many of these are based on the use of natural compounds such as metabolites and phenols, and also proteins such as antibodies and chaperones.

This Special Issue will cover updated research on the natural inhibitors of neurodegenerative amyloid aggregation, such as small molecules and antibodies. Its scope is multidisciplinary, hosting contributions based on biochemical, biophysical and computational approaches. It will encompass experimentations performed in vitro as well as in cellular and animal models, including those aimed at manipulating the protein homeostasis system.

Prof. Dr. Paolo Tortora
Dr. Francesco A. Aprile
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Neurodegeneration
  • Protein aggregation
  • Small molecules
  • Peptides
  • Protein therapeutics
  • Antibodies

Published Papers (6 papers)

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Editorial

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4 pages, 196 KiB  
Editorial
Natural Inhibitors of Amyloid Aggregation
by Paolo Tortora and Francesco A. Aprile
Int. J. Mol. Sci. 2023, 24(17), 13310; https://doi.org/10.3390/ijms241713310 - 28 Aug 2023
Viewed by 797
Abstract
Amyloid aggregates are diverse proteinaceous assemblies, including one or more protein species, wherein the molecules interact according to characteristic patterns [...] Full article
(This article belongs to the Special Issue Natural Inhibitors of Amyloid Aggregation)

Research

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16 pages, 2795 KiB  
Article
Hydroxytyrosol Inhibits Protein Oligomerization and Amyloid Aggregation in Human Insulin
by Ivana Sirangelo, Margherita Borriello, Silvia Vilasi and Clara Iannuzzi
Int. J. Mol. Sci. 2020, 21(13), 4636; https://doi.org/10.3390/ijms21134636 - 30 Jun 2020
Cited by 19 | Viewed by 2588
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Natural Inhibitors of Amyloid Aggregation)
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Graphical abstract

15 pages, 1501 KiB  
Article
The Impact of Natural Compounds on S-Shaped Aβ42 Fibril: From Molecular Docking to Biophysical Characterization
by Stefano Muscat, Lorenzo Pallante, Filip Stojceski, Andrea Danani, Gianvito Grasso and Marco Agostino Deriu
Int. J. Mol. Sci. 2020, 21(6), 2017; https://doi.org/10.3390/ijms21062017 - 16 Mar 2020
Cited by 17 | Viewed by 3764
Abstract
The pursuit for effective strategies inhibiting the amyloidogenic process in neurodegenerative disorders, such as Alzheimer’s disease (AD), remains one of the main unsolved issues, and only a few drugs have demonstrated to delay the degeneration of the cognitive system. Moreover, most therapies induce [...] Read more.
The pursuit for effective strategies inhibiting the amyloidogenic process in neurodegenerative disorders, such as Alzheimer’s disease (AD), remains one of the main unsolved issues, and only a few drugs have demonstrated to delay the degeneration of the cognitive system. Moreover, most therapies induce severe side effects and are not effective at all stages of the illness. The need to find novel and reliable drugs appears therefore of primary importance. In this context, natural compounds have shown interesting beneficial effects on the onset and progression of neurodegenerative diseases, exhibiting a great inhibitory activity on the formation of amyloid aggregates and proving to be effective in many preclinical and clinical studies. However, their inhibitory mechanism is still unclear. In this work, ensemble docking and molecular dynamics simulations on S-shaped Aβ42 fibrils have been carried out to evaluate the influence of several natural compounds on amyloid conformational behaviour. A deep understanding of the interaction mechanisms between natural compounds and Aβ aggregates may play a key role to pave the way for design, discovery and optimization strategies toward an efficient destabilization of toxic amyloid assemblies. Full article
(This article belongs to the Special Issue Natural Inhibitors of Amyloid Aggregation)
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Graphical abstract

25 pages, 11912 KiB  
Article
The Aggregation Conditions Define Whether EGCG is an Inhibitor or Enhancer of α-Synuclein Amyloid Fibril Formation
by Rebecca Sternke-Hoffmann, Alessia Peduzzo, Najoua Bolakhrif, Rainer Haas and Alexander K. Buell
Int. J. Mol. Sci. 2020, 21(6), 1995; https://doi.org/10.3390/ijms21061995 - 14 Mar 2020
Cited by 20 | Viewed by 3559
Abstract
The amyloid fibril formation by α -synuclein is a hallmark of various neurodegenerative disorders, most notably Parkinson’s disease. Epigallocatechin gallate (EGCG) has been reported to be an efficient inhibitor of amyloid formation by numerous proteins, among them α -synuclein. Here, we show that [...] Read more.
The amyloid fibril formation by α -synuclein is a hallmark of various neurodegenerative disorders, most notably Parkinson’s disease. Epigallocatechin gallate (EGCG) has been reported to be an efficient inhibitor of amyloid formation by numerous proteins, among them α -synuclein. Here, we show that this applies only to a small region of the relevant parameter space, in particular to solution conditions where EGCG readily oxidizes, and we find that the oxidation product is a much more potent inhibitor compared to the unmodified EGCG. In addition to its inhibitory effects, EGCG and its oxidation products can under some conditions even accelerate α -synuclein amyloid fibril formation through facilitating its heterogeneous primary nucleation. Furthermore, we show through quantitative seeding experiments that, contrary to previous reports, EGCG is not able to re-model α -synuclein amyloid fibrils into seeding-incompetent structures. Taken together, our results paint a complex picture of EGCG as a compound that can under some conditions inhibit the amyloid fibril formation of α -synuclein, but the inhibitory action is not robust against various physiologically relevant changes in experimental conditions. Our results are important for the development of strategies to identify and characterize promising amyloid inhibitors. Full article
(This article belongs to the Special Issue Natural Inhibitors of Amyloid Aggregation)
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Review

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19 pages, 2502 KiB  
Review
Human-Induced Pluripotent Stem Cells and Herbal Small-Molecule Drugs for Treatment of Alzheimer’s Disease
by Wei Wuli, Sheng-Tzung Tsai, Tzyy-Wen Chiou and Horng-Jyh Harn
Int. J. Mol. Sci. 2020, 21(4), 1327; https://doi.org/10.3390/ijms21041327 - 16 Feb 2020
Cited by 11 | Viewed by 4837
Abstract
Alzheimer’s disease (AD) is characterized by extracellular amyloid plaques composed of the β-amyloid peptides and intracellular neurofibrillary tangles and associates with progressive declines in memory and cognition. Several genes play important roles and regulate enzymes that produce a pathological accumulation of β-amyloid in [...] Read more.
Alzheimer’s disease (AD) is characterized by extracellular amyloid plaques composed of the β-amyloid peptides and intracellular neurofibrillary tangles and associates with progressive declines in memory and cognition. Several genes play important roles and regulate enzymes that produce a pathological accumulation of β-amyloid in the brain, such as gamma secretase (γ-secretase). Induced pluripotent stem cells from patients with Alzheimer’s disease with different underlying genetic mechanisms may help model different phenotypes of Alzheimer’s disease and facilitate personalized drug screening platforms for the identification of small molecules. We also discuss recent developments by γ-secretase inhibitors and modulators in the treatment of AD. In addition, small-molecule drugs isolated from Chinese herbal medicines have been shown effective in treating Alzheimer’s disease. We propose a mechanism of small-molecule drugs in treating Alzheimer’s disease. Combining therapy with different small-molecule drugs may increase the chance of symptomatic treatment. A customized strategy tailored to individuals and in combination with therapy may be a more suitable treatment option for Alzheimer’s disease in the future. Full article
(This article belongs to the Special Issue Natural Inhibitors of Amyloid Aggregation)
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40 pages, 2345 KiB  
Review
Healthy Effects of Plant Polyphenols: Molecular Mechanisms
by Manuela Leri, Maria Scuto, Maria Laura Ontario, Vittorio Calabrese, Edward J. Calabrese, Monica Bucciantini and Massimo Stefani
Int. J. Mol. Sci. 2020, 21(4), 1250; https://doi.org/10.3390/ijms21041250 - 13 Feb 2020
Cited by 261 | Viewed by 15588
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Natural Inhibitors of Amyloid Aggregation)
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