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Understanding Amyloid Structures and Disease: A Continuing Challenge in Health Research

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

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 31796

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Guest Editor
Department of Pathology, University of Pisa, 56100 Pisa, Italy
Interests: metabolic biochemistry; thyroid hormone analogs and metabolites; vitamin D analogs; drug design, synthesis and development
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Special Issue Information

Dear Colleagues,

The aggregation of a polypeptide chain into amyloid fibrils and their accumulation and deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. Amyloidosis occurs in association with many pathological conditions that may be also linked to aging, such as Alzheimer's disease, Parkinson's disease, type II diabetes, and dialysis-related amyloidosis.

Amyloidogenic proteins are relatively small, typically soluble, and intrinsically disordered proteins that undergo remarkable conformational re-arrangements associated with a process of aggregation and self‐assembly that leads ultimately to the formation of fibrillar aggregates designated as amyloid fibrils. Even though recent years have witnessed an increasing interest in the self‐assembly of amyloidogenic proteins, with growing numbers of multidisciplinary scientific approaches (including experimental, theoretical, and computational tools), the elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and the mechanisms relating fibril formation to disease have remained elusive.

Over the last few decades, there have been extensive efforts to develop novel inhibitors and modulators as potential therapeutics for amyloidogenic protein aggregation and the development of amyloid disease. Up to the present, however, drug therapies have been used to provide almost exclusively symptomatic benefits, but have failed to prevent or delay the onset of the disease. Therefore, there is a sense that therapeutic innovation is needed in order to effectively address the development and progression of the great diversity of amyloid diseases.

In this Special Issue, “Understanding amyloid structures and disease: a continuing challenge in health research,” we invite investigators to contribute original research articles and review articles to advance our knowledge in the molecular mechanisms of amyloidogenic protein aggregation and activity, as well as to provide new insights on the development of new therapeutic strategies for the prevention of amyloid diseases. It is our hope that this Special Issue will assist current and future generations of scientists in translating scientific findings into new treatments to effectively delay the onset or slow the progression of amyloid diseases.

Dr. Grazia Chiellini
Guest Editor

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Published Papers (10 papers)

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Editorial

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4 pages, 184 KiB  
Editorial
Understanding Amyloid Structures and Disease: A Continuing Challenge in Health Research
by Grazia Chiellini
Int. J. Mol. Sci. 2021, 22(12), 6620; https://doi.org/10.3390/ijms22126620 - 21 Jun 2021
Cited by 3 | Viewed by 1788
Abstract
Neurodegenerative disorders (NDDs), including Alzheimer’s, Parkinson’s, and Huntington’s diseases, are a highly prevalent class of disorders that share the presence of aberrant aggregates called amyloids in the nervous system [...] Full article

Research

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15 pages, 1851 KiB  
Article
Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis
by Bokyung Kim, Young Ho Ko, Massimiliano Runfola, Simona Rapposelli, Gabriella Ortore, Grazia Chiellini and Jin Hae Kim
Int. J. Mol. Sci. 2021, 22(7), 3488; https://doi.org/10.3390/ijms22073488 - 28 Mar 2021
Cited by 6 | Viewed by 3184
Abstract
Thyromimetics, whose physicochemical characteristics are analog to thyroid hormones (THs) and their derivatives, are promising candidates as novel therapeutics for neurodegenerative and metabolic pathologies. In particular, sobetirome (GC-1), one of the initial halogen-free thyromimetics, and newly synthesized IS25 and TG68, with optimized ADME-Tox [...] Read more.
Thyromimetics, whose physicochemical characteristics are analog to thyroid hormones (THs) and their derivatives, are promising candidates as novel therapeutics for neurodegenerative and metabolic pathologies. In particular, sobetirome (GC-1), one of the initial halogen-free thyromimetics, and newly synthesized IS25 and TG68, with optimized ADME-Tox profile, have recently attracted attention owing to their superior therapeutic benefits, selectivity, and enhanced permeability. Here, we further explored the functional capabilities of these thyromimetics to inhibit transthyretin (TTR) amyloidosis. TTR is a homotetrameric transporter protein for THs, yet it is also responsible for severe amyloid fibril formation, which is facilitated by tetramer dissociation into non-native monomers. By combining nuclear magnetic resonance (NMR) spectroscopy, computational simulation, and biochemical assays, we found that GC-1 and newly designed diphenyl-methane-based thyromimetics, namely IS25 and TG68, are TTR stabilizers and efficient suppressors of TTR aggregation. Based on these observations, we propose the novel potential of thyromimetics as a multi-functional therapeutic molecule for TTR-related pathologies, including neurodegenerative diseases. Full article
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15 pages, 3986 KiB  
Article
Pseudopeptide Amyloid Aggregation Inhibitors: In Silico, Single Molecule and Cell Viability Studies
by Morgan Robinson, Jennifer Lou, Banafsheh Mehrazma, Arvi Rauk, Michael Beazely and Zoya Leonenko
Int. J. Mol. Sci. 2021, 22(3), 1051; https://doi.org/10.3390/ijms22031051 - 21 Jan 2021
Cited by 11 | Viewed by 2638
Abstract
Neurodegeneration in Alzheimer’s disease (AD) is defined by pathology featuring amyloid-β (Aβ) deposition in the brain. Aβ monomers themselves are generally considered to be nontoxic, but misfold into β-sheets and aggregate to form neurotoxic oligomers. One suggested strategy to treat AD is to [...] Read more.
Neurodegeneration in Alzheimer’s disease (AD) is defined by pathology featuring amyloid-β (Aβ) deposition in the brain. Aβ monomers themselves are generally considered to be nontoxic, but misfold into β-sheets and aggregate to form neurotoxic oligomers. One suggested strategy to treat AD is to prevent the formation of toxic oligomers. The SG inhibitors are a class of pseudopeptides designed and optimized using molecular dynamics (MD) simulations for affinity to Aβ and experimentally validated for their ability to inhibit amyloid-amyloid binding using single molecule force spectroscopy (SMFS). In this work, we provide a review of our previous MD and SMFS studies of these inhibitors and present new cell viability studies that demonstrate their neuroprotective effects against Aβ(1–42) oligomers using mouse hippocampal-derived HT22 cells. Two of the tested SG inhibitors, predicted to bind Aβ in anti-parallel orientation, demonstrated neuroprotection against Aβ(1–42). A third inhibitor, predicted to bind parallel to Aβ, was not neuroprotective. Myristoylation of SG inhibitors, intended to enhance delivery across the blood-brain barrier (BBB), resulted in cytotoxicity. This is the first use of HT22 cells for the study of peptide aggregation inhibitors. Overall, this work will inform the future development of peptide aggregation inhibitors against Aβ toxicity. Full article
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16 pages, 2459 KiB  
Article
Aβ Beyond the AD Pathology: Exploring the Structural Response of Membranes Exposed to Nascent Aβ Peptide
by Valeria Rondelli, Mario Salmona, Laura Colombo, Giovanna Fragneto, Giulia C. Fadda, Laura Cantu’ and Elena Del Favero
Int. J. Mol. Sci. 2020, 21(21), 8295; https://doi.org/10.3390/ijms21218295 - 5 Nov 2020
Cited by 7 | Viewed by 2074
Abstract
The physiological and pathological roles of nascent amyloid beta (Aβ) monomers are still debated in the literature. Their involvement in the pathological route of Alzheimer’s Disease (AD) is currently considered to be the most relevant, triggered by their aggregation into structured oligomers, a [...] Read more.
The physiological and pathological roles of nascent amyloid beta (Aβ) monomers are still debated in the literature. Their involvement in the pathological route of Alzheimer’s Disease (AD) is currently considered to be the most relevant, triggered by their aggregation into structured oligomers, a toxic species. Recently, it has been suggested that nascent Aβ, out of the amyloidogenic pathway, plays a physiological and protective role, especially in the brain. In this emerging perspective, the study presented in this paper investigated whether the organization of model membranes is affected by contact with Aβ in the nascent state, as monomers. The outcome is that, notably, the rules of engagement and the resulting structural outcome are dictated by the composition and properties of the membrane, rather than by the Aβ variant. Interestingly, Aβ monomers are observed to favor the tightening of adjacent complex membranes, thereby affecting a basic structural event for cell-cell adhesion and cell motility. Full article
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23 pages, 5531 KiB  
Article
Alpha-B-Crystallin Effect on Mature Amyloid Fibrils: Different Degradation Mechanisms and Changes in Cytotoxicity
by Olga V. Stepanenko, M. I. Sulatsky, E. V. Mikhailova, Olesya V. Stepanenko, O. I. Povarova, I. M. Kuznetsova, K. K. Turoverov and A. I. Sulatskaya
Int. J. Mol. Sci. 2020, 21(20), 7659; https://doi.org/10.3390/ijms21207659 - 16 Oct 2020
Cited by 13 | Viewed by 3302
Abstract
Given the ability of molecular chaperones and chaperone-like proteins to inhibit the formation of pathological amyloid fibrils, the chaperone-based therapy of amyloidosis has recently been proposed. However, since these diseases are often diagnosed at the stages when a large amount of amyloids is [...] Read more.
Given the ability of molecular chaperones and chaperone-like proteins to inhibit the formation of pathological amyloid fibrils, the chaperone-based therapy of amyloidosis has recently been proposed. However, since these diseases are often diagnosed at the stages when a large amount of amyloids is already accumulated in the patient’s body, in this work we pay attention to the undeservedly poorly studied problem of chaperone and chaperone-like proteins’ effect on mature amyloid fibrils. We showed that a heat shock protein alpha-B-crystallin, which is capable of inhibiting fibrillogenesis and is found in large quantities as a part of amyloid plaques, can induce degradation of mature amyloids by two different mechanisms. Under physiological conditions, alpha-B-crystallin induces fluffing and unweaving of amyloid fibrils, which leads to a partial decrease in their structural ordering without lowering their stability and can increase their cytotoxicity. We found a higher correlation between the rate and effectiveness of amyloids degradation with the size of fibrils clusters rather than with amino acid sequence of amyloidogenic protein. Some external effects (such as an increase in medium acidity) can lead to a change in the mechanism of fibrils degradation induced by alpha-B-crystallin: amyloid fibers are fragmented without changing their secondary structure and properties. According to recent data, fibrils cutting can lead to the generation of seeds for new bona fide amyloid fibrils and accelerate the accumulation of amyloids, as well as enhance the ability of fibrils to disrupt membranes and to reduce cell viability. Our results emphasize the need to test the chaperone effect not only on fibrillogenesis, but also on the mature amyloid fibrils, including stress conditions, in order to avoid undesirable disease progression during chaperone-based therapy. Full article
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17 pages, 2927 KiB  
Article
Development of Conformational Antibodies to Detect Bcl-xL’s Amyloid Aggregates in Metal-Induced Apoptotic Neuroblastoma Cells
by Alexis Gonneaud, Fatima-Zohra Fakhir, Emeline Landas, Enora Le Tallec, Elisabeth Chartier-Garcia, Christine Almunia, Alexandre Chenal, Vincent Forge and Christel Marquette
Int. J. Mol. Sci. 2020, 21(20), 7625; https://doi.org/10.3390/ijms21207625 - 15 Oct 2020
Cited by 3 | Viewed by 3079
Abstract
Bcl-xL, a member of the Bcl-2 family, is a pro-survival protein involved in apoptosis regulation. We have previously reported the ability of Bcl-xL to form various types of fibers, from native to amyloid conformations. Here, we have mimicked the effect of apoptosis-induced caspase [...] Read more.
Bcl-xL, a member of the Bcl-2 family, is a pro-survival protein involved in apoptosis regulation. We have previously reported the ability of Bcl-xL to form various types of fibers, from native to amyloid conformations. Here, we have mimicked the effect of apoptosis-induced caspase activity on Bcl-xL by limited proteolysis using trypsin. We show that cleaved Bcl-xL (ΔN-Bcl-xL) forms fibers that exhibit the features of amyloid structures (BclxLcf37). Moreover, three monoclonal antibodies (mAbs), produced by mouse immunization and directed against ΔN-Bcl-xL or Bcl-xL fibers, were selected and characterized. Our results show that these mAbs specifically target ΔN-Bcl-xL in amyloid fibers in vitro. Upon metal-stress-induced apoptosis, these mAbs are able to detect the presence of Bcl-xL in amyloid aggregates in neuroblastoma SH-SY5Y cell lines. In conclusion, these specific mAbs directed against amyloidogenic conformations of Bcl-xL constitute promising tools for studying, in vitro and in cellulo, the contribution of Bcl-xL in apoptosis. These mAbs may further help in developing new diagnostics and therapies, considering Bcl-xL as a strategic target for treating brain lesions relevant to stroke and neurodegenerative diseases. Full article
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15 pages, 2547 KiB  
Article
Dietary Intake of Rosmarinic Acid Increases Serum Inhibitory Activity in Amyloid A Aggregation and Suppresses Deposition in the Organs of Mice
by Xuguang Lin, Kenichi Watanabe, Masahiro Kuragano, Yukina Kurotaki, Ushio Nakanishi and Kiyotaka Tokuraku
Int. J. Mol. Sci. 2020, 21(17), 6031; https://doi.org/10.3390/ijms21176031 - 21 Aug 2020
Cited by 10 | Viewed by 3229
Abstract
Serum amyloid A (SAA) is one of the most important precursor amyloid proteins and plays a vital step in AA amyloidosis, although the underlying aggregation mechanism has not been elucidated. Since SAA aggregation is a key step in this pathogenesis, inhibitors are useful [...] Read more.
Serum amyloid A (SAA) is one of the most important precursor amyloid proteins and plays a vital step in AA amyloidosis, although the underlying aggregation mechanism has not been elucidated. Since SAA aggregation is a key step in this pathogenesis, inhibitors are useful to prevent and treat AA amyloidosis, serving as tools to investigate the pathogenic mechanism. In this study, we showed that rosmarinic acid (RA), which is a well-known inhibitor of the aggregation of amyloid β (Aβ), displayed inhibitory activity against SAA aggregation in vitro using a microliter-scale high-throughput screening (MSHTS) system with quantum-dot nanoprobes. Therefore, we evaluated the amyloid aggregation inhibitory activity of blood and the deposition of SAA in organs by feeding mice with Melissa officinalis extract (ME) containing RA as an active substance. Interestingly, the inhibitory activity of ME-fed mice sera for SAA and Aβ aggregation, measured with the MSHTS system, was higher than that of the control group. The amount of amyloid deposition in the organs of ME-fed mice was lower than that in the control group, suggesting that the SAA aggregation inhibitory activity of serum is associated with SAA deposition. These results suggest that dietary intake of RA-containing ME enhanced amyloid aggregation inhibitory activity of blood and suppressed SAA deposition in organs. This study also demonstrated that the MSHTS system could be applied to in vitro screening and to monitor comprehensive activity of metabolized foods adsorbed by blood. Full article
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Review

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22 pages, 2482 KiB  
Review
The Diagnostic Potential of Amyloidogenic Proteins
by Yiyun Jin, Devkee Mahesh Vadukul, Dimitra Gialama, Ying Ge, Rebecca Thrush, Joe Thomas White and Francesco Antonio Aprile
Int. J. Mol. Sci. 2021, 22(8), 4128; https://doi.org/10.3390/ijms22084128 - 16 Apr 2021
Cited by 7 | Viewed by 3500
Abstract
Neurodegenerative disorders are a highly prevalent class of diseases, whose pathological mechanisms start before the appearance of any clear symptoms. This fact has prompted scientists to search for biomarkers that could aid early treatment. These currently incurable pathologies share the presence of aberrant [...] Read more.
Neurodegenerative disorders are a highly prevalent class of diseases, whose pathological mechanisms start before the appearance of any clear symptoms. This fact has prompted scientists to search for biomarkers that could aid early treatment. These currently incurable pathologies share the presence of aberrant aggregates called amyloids in the nervous system, which are composed of specific proteins. In this review, we discuss how these proteins, their conformations and modifications could be exploited as biomarkers for diagnostic purposes. We focus on proteins that are associated with the most prevalent neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, and frontotemporal dementia. We also describe current challenges in detection, the most recent techniques with diagnostic potentials and possible future developments in diagnosis. Full article
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30 pages, 5974 KiB  
Review
Space-Dependent Glia–Neuron Interplay in the Hippocampus of Transgenic Models of β-Amyloid Deposition
by Daniele Lana, Filippo Ugolini and Maria Grazia Giovannini
Int. J. Mol. Sci. 2020, 21(24), 9441; https://doi.org/10.3390/ijms21249441 - 11 Dec 2020
Cited by 10 | Viewed by 3632
Abstract
This review is focused on the description and discussion of the alterations of astrocytes and microglia interplay in models of Alzheimer’s disease (AD). AD is an age-related neurodegenerative pathology with a slowly progressive and irreversible decline of cognitive functions. One of AD’s histopathological [...] Read more.
This review is focused on the description and discussion of the alterations of astrocytes and microglia interplay in models of Alzheimer’s disease (AD). AD is an age-related neurodegenerative pathology with a slowly progressive and irreversible decline of cognitive functions. One of AD’s histopathological hallmarks is the deposition of amyloid beta (Aβ) plaques in the brain. Long regarded as a non-specific, mere consequence of AD pathology, activation of microglia and astrocytes is now considered a key factor in both initiation and progression of the disease, and suppression of astrogliosis exacerbates neuropathology. Reactive astrocytes and microglia overexpress many cytokines, chemokines, and signaling molecules that activate or damage neighboring cells and their mutual interplay can result in virtuous/vicious cycles which differ in different brain regions. Heterogeneity of glia, either between or within a particular brain region, is likely to be relevant in healthy conditions and disease processes. Differential crosstalk between astrocytes and microglia in CA1 and CA3 areas of the hippocampus can be responsible for the differential sensitivity of the two areas to insults. Understanding the spatial differences and roles of glia will allow us to assess how these interactions can influence the state and progression of the disease, and will be critical for identifying therapeutic strategies. Full article
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13 pages, 3031 KiB  
Review
Transthyretin Stabilization: An Emerging Strategy for the Treatment of Alzheimer’s Disease?
by Federica Saponaro, Jin Hae Kim and Grazia Chiellini
Int. J. Mol. Sci. 2020, 21(22), 8672; https://doi.org/10.3390/ijms21228672 - 17 Nov 2020
Cited by 22 | Viewed by 4469
Abstract
Transthyretin (TTR), previously named prealbumin is a plasma protein secreted mainly by the liver and choroid plexus (CP) that is a carrier for thyroid hormones (THs) and retinol (vitamin A). The structure of TTR, with four monomers rich in β-chains in a globular [...] Read more.
Transthyretin (TTR), previously named prealbumin is a plasma protein secreted mainly by the liver and choroid plexus (CP) that is a carrier for thyroid hormones (THs) and retinol (vitamin A). The structure of TTR, with four monomers rich in β-chains in a globular tetrameric protein, accounts for the predisposition of the protein to aggregate in fibrils, leading to a rare and severe disease, namely transthyretin amyloidosis (ATTR). Much effort has been made and still is required to find new therapeutic compounds that can stabilize TTR (“kinetic stabilization”) and prevent the amyloid genetic process. Moreover, TTR is an interesting therapeutic target for neurodegenerative diseases due to its recognized neuroprotective properties in the cognitive impairment context and interestingly in Alzheimer’s disease (AD). Much evidence has been collected regarding the neuroprotective effects in AD, including through in vitro and in vivo studies as well as a wide range of clinical series. Despite this supported hypothesis of neuroprotection for TTR, the mechanisms are still not completely clear. The aim of this review is to highlight the most relevant findings on the neuroprotective role of TTR, and to summarize the recent progress on the development of TTR tetramer stabilizers. Full article
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