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Molecular Structure and Mechanisms of Neurotoxicity of Amyloid Prefibrillar Oligomers

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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 2022) | Viewed by 15517

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Special Issue Editors

Prof. Dr. Marco Diociaiuti

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Guest Editor

Istituto Superiore Di Sanita, Rome, Centro Nazionale Malattie Rare, Rome, Italy
Interests: membrane lipids; membrane channels

Prof. Dr. Claudio Frank

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Co-Guest Editor

Physiology in Medicine and Surgery, Saint Camillus International University of Health Sciences, Rome, Italy

Special Issue Information

Dear Colleagues,

Since 2003, it has been proposed that a common core of pathologic pathways exists for amyloid-associated diseases based on the cellular membrane permeabilization and subsequent abnormal Ca²⁺-influx induced by aggregates of the involved proteins, independently from their primary sequence. An intriguing hypothesis has been formulated, that amyloid diseases were caused by aggregates that mimic bacterial pore-forming toxins, which, in general, form well-ordered oligomeric membrane-spanning pores. Up until now, emerging evidence has been focused on low molecular weight prefibrillar oligomers (PFOs) as the toxic species. On the other hand, many studies have indicated that the neuronal membrane composition and its chemical microenvironment play a pivotal role. It has been shown that the brains of AD patients contain increased fractions of anionic lipids, and that anionic lipids and not neutral lipids favor cationic influx. It is now generally accepted that “lipid-rafts”, which are ordered nanodomains formed by sphingolipids and are cholesterol abundant in the outer leaflet of the plasma membrane, play a special role. It has been also reported the involvement of ionotropic glutamate receptors NMDA, the uncontrolled activation of which would promote an abnormal Ca²⁺ influx. However, the existence of a specific common toxic structure, and a common mechanism by which it induces neuronal damage and death, is still an open hypothesis.

The purpose of this Special Issue is to gather as much information to test this hypothesis. Greater knowledge of the molecular structure of amyloid PFOs and their interaction with lipid membranes, also through computational approaches, is the basis of the design of molecules able to prevent and/or inhibit neuronal damage and death. Moreover, verification of the general nature of the hypothesis could open new possibilities in the cure of important diseases belonging to the large family of amyloid neurodegenerations. Original research articles, reviews, and letters on these topics are welcome in this Special Issue.

Prof. Dr. Marco Diociaiuti
Guest Editor
Prof. Dr. Claudio Frank
Co-Guest Editor

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Published Papers (5 papers)

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Research

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21 pages, 2275 KiB

Open AccessArticle

Modulation of Amyloid β-Induced Microglia Activation and Neuronal Cell Death by Curcumin and Analogues

by Ersilia De Lorenzi, Davide Franceschini, Cecilia Contardi, Rita Maria Concetta Di Martino, Francesca Seghetti, Massimo Serra, Federica Bisceglia, Andrea Pagetta, Morena Zusso and Federica Belluti

Int. J. Mol. Sci. 2022, 23(8), 4381; https://doi.org/10.3390/ijms23084381 - 15 Apr 2022

Cited by 8 | Viewed by 2451

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is not restricted to the neuronal compartment but includes important interactions with immune cells, including microglia. Protein aggregates, common pathological hallmarks of AD, bind to pattern recognition receptors on microglia and trigger an inflammatory response, which contributes to disease progression and severity. In this context, curcumin is emerging as a potential drug candidate able to affect multiple key pathways implicated in AD, including neuroinflammation. Therefore, we studied the effect of curcumin and its structurally related analogues cur6 and cur16 on amyloid-β (Aβ)-induced microglia activation and neuronal cell death, as well as their effect on the modulation of Aβ aggregation. Primary cortical microglia and neurons were exposed to two different populations of Aβ42 oligomers (Aβ42Os) where the oligomeric state had been assigned by capillary electrophoresis and ultrafiltration. When stimulated with high molecular weight Aβ42Os, microglia released proinflammatory cytokines that led to early neuronal cell death. The studied compounds exerted an anti-inflammatory effect on high molecular weight Aβ42O-stimulated microglia and possibly inhibited microglia-mediated neuronal cell toxicity. Furthermore, the tested compounds demonstrated antioligomeric activity during the process of in vitro Aβ42 aggregation. These findings could be investigated further and used for the optimization of multipotent candidate molecules for AD treatment Full article

(This article belongs to the Special Issue Molecular Structure and Mechanisms of Neurotoxicity of Amyloid Prefibrillar Oligomers)

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11 pages, 2475 KiB

Open AccessArticle

Live Cell FRET Imaging Reveals Amyloid β-Peptide Oligomerization in Hippocampal Neurons

by Yang Gao, Stefan Wennmalm, Bengt Winblad, Sophia Schedin-Weiss and Lars O. Tjernberg

Int. J. Mol. Sci. 2021, 22(9), 4530; https://doi.org/10.3390/ijms22094530 - 26 Apr 2021

Cited by 3 | Viewed by 2642

Abstract

Amyloid β-peptide (Aβ) oligomerization is believed to contribute to the neuronal dysfunction in Alzheimer disease (AD). Despite decades of research, many details of Aβ oligomerization in neurons still need to be revealed. Förster resonance energy transfer (FRET) is a simple but effective way to study molecular interactions. Here, we used a confocal microscope with a sensitive Airyscan detector for FRET detection. By live cell FRET imaging, we detected Aβ42 oligomerization in primary neurons. The neurons were incubated with fluorescently labeled Aβ42 in the cell culture medium for 24 h. Aβ42 were internalized and oligomerized in the lysosomes/late endosomes in a concentration-dependent manner. Both the cellular uptake and intracellular oligomerization of Aβ42 were significantly higher than for Aβ40. These findings provide a better understanding of Aβ42 oligomerization in neurons. Full article

(This article belongs to the Special Issue Molecular Structure and Mechanisms of Neurotoxicity of Amyloid Prefibrillar Oligomers)

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15 pages, 2582 KiB

Open AccessArticle

Role of Electrostatic Interactions in Calcitonin Prefibrillar Oligomer-Induced Amyloid Neurotoxicity and Protective Effect of Neuraminidase

by Ida Cariati, Roberto Bonanni, Mario Marini, Anna Maria Rinaldi, Beatrice Zarrilli, Virginia Tancredi, Claudio Frank, Giovanna D’Arcangelo and Marco Diociaiuti

Int. J. Mol. Sci. 2021, 22(8), 3947; https://doi.org/10.3390/ijms22083947 - 11 Apr 2021

Cited by 3 | Viewed by 1791

Abstract

Salmon calcitonin is a good model for studying amyloid behavior and neurotoxicity. Its slow aggregation rate allows the purification of low molecular weight prefibrillar oligomers, which are the most toxic species. It has been proposed that these species may cause amyloid pore formation in neuronal membranes through contact with negatively charged sialic acid residues of the ganglioside GM1. In particular, it has been proposed that an electrostatic interaction may be responsible for the initial contact between prefibrillar oligomers and GM1 contained in lipid rafts. Based on this evidence, the aim of our work was to investigate whether the neurotoxic action induced by calcitonin prefibrillar oligomers could be counteracted by treatment with neuraminidase, an enzyme that removes sialic acid residues from gangliosides. Therefore, we studied cell viability in HT22 cell lines and evaluated the effects on synaptic transmission and long-term potentiation by in vitro extracellular recordings in mouse hippocampal slices. Our results showed that treatment with neuraminidase alters the surface charges of lipid rafts, preventing interaction between the calcitonin prefibrillar oligomers and GM1, and suggesting that the enzyme, depending on the concentration used, may have a partial or total protective action in terms of cell survival and modulation of synaptic transmission. Full article

(This article belongs to the Special Issue Molecular Structure and Mechanisms of Neurotoxicity of Amyloid Prefibrillar Oligomers)

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Review

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31 pages, 6007 KiB

Open AccessReview

Amyloid Prefibrillar Oligomers: The Surprising Commonalities in Their Structure and Activity

by Marco Diociaiuti, Roberto Bonanni, Ida Cariati, Claudio Frank and Giovanna D’Arcangelo

Int. J. Mol. Sci. 2021, 22(12), 6435; https://doi.org/10.3390/ijms22126435 - 16 Jun 2021

Cited by 15 | Viewed by 3125

Abstract

It has been proposed that a “common core” of pathologic pathways exists for the large family of amyloid-associated neurodegenerations, including Alzheimer’s, Parkinson’s, type II diabetes and Creutzfeldt–Jacob’s Disease. Aggregates of the involved proteins, independently from their primary sequence, induced neuron membrane permeabilization able to trigger an abnormal Ca²⁺ influx leading to synaptotoxicity, resulting in reduced expression of synaptic proteins and impaired synaptic transmission. Emerging evidence is now focusing on low-molecular-weight prefibrillar oligomers (PFOs), which mimic bacterial pore-forming toxins that form well-ordered oligomeric membrane-spanning pores. At the same time, the neuron membrane composition and its chemical microenvironment seem to play a pivotal role. In fact, the brain of AD patients contains increased fractions of anionic lipids able to favor cationic influx. However, up to now the existence of a specific “common structure” of the toxic aggregate, and a “common mechanism” by which it induces neuronal damage, synaptotoxicity and impaired synaptic transmission, is still an open hypothesis. In this review, we gathered information concerning this hypothesis, focusing on the proteins linked to several amyloid diseases. We noted commonalities in their structure and membrane activity, and their ability to induce Ca²⁺ influx, neurotoxicity, synaptotoxicity and impaired synaptic transmission. Full article

(This article belongs to the Special Issue Molecular Structure and Mechanisms of Neurotoxicity of Amyloid Prefibrillar Oligomers)

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21 pages, 827 KiB

Open AccessReview

An Unbalanced Synaptic Transmission: Cause or Consequence of the Amyloid Oligomers Neurotoxicity?

by Miriam Sciaccaluga, Alfredo Megaro, Giovanni Bellomo, Gabriele Ruffolo, Michele Romoli, Eleonora Palma and Cinzia Costa

Int. J. Mol. Sci. 2021, 22(11), 5991; https://doi.org/10.3390/ijms22115991 - 1 Jun 2021

Cited by 29 | Viewed by 4365

Abstract

Amyloid-β (Aβ) 1-40 and 1-42 peptides are key mediators of synaptic and cognitive dysfunction in Alzheimer’s disease (AD). Whereas in AD, Aβ is found to act as a pro-epileptogenic factor even before plaque formation, amyloid pathology has been detected among patients with epilepsy with increased risk of developing AD. Among Aβ aggregated species, soluble oligomers are suggested to be responsible for most of Aβ’s toxic effects. Aβ oligomers exert extracellular and intracellular toxicity through different mechanisms, including interaction with membrane receptors and the formation of ion-permeable channels in cellular membranes. These damages, linked to an unbalance between excitatory and inhibitory neurotransmission, often result in neuronal hyperexcitability and neural circuit dysfunction, which in turn increase Aβ deposition and facilitate neurodegeneration, resulting in an Aβ-driven vicious loop. In this review, we summarize the most representative literature on the effects that oligomeric Aβ induces on synaptic dysfunction and network disorganization. Full article

(This article belongs to the Special Issue Molecular Structure and Mechanisms of Neurotoxicity of Amyloid Prefibrillar Oligomers)

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Molecular Structure and Mechanisms of Neurotoxicity of Amyloid Prefibrillar Oligomers

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