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Role of Amyloid Protein in Neurological Diseases

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Structure and Dynamics".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 13990

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Special Issue Editors

Prof. Dr. Chuanhai Cao

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Guest Editor

Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA
Interests: Alzheimer’s disease; Parkinson’s disease; immunology; nutraceuticals; peptide-sensitized dendritic cells vaccine for neurological disease treatment
Special Issues, Collections and Topics in MDPI journals

Dr. Haifan Wu

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Guest Editor

Department of Chemistry, Fairmount College of Liberal Arts and Sciences, Wichita State University, Wichita, KS 67260, USA
Interests: protein misfolding; neuro-inflammation; peptide/protein therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The ability of the amyloid protein to change its secondary structure and manifest as an insoluble fibrous protein in the amyloidosis process is often detrimental and plays a crucial role in various neurodegenerative diseases. In this Special Issue, edited by Dr. Chuanhai Cao, research papers and review articles that examine the structural properties of amyloid beta, isoform changes of amyloid, amyloidosis, and their consequent biological and physiological effects are welcome. Although Alzheimer’s disease (AD) is the most frequent type of amyloidosis seen in humans, the interplay between misfolded amyloid proteins and disease are not limited to AD. In fact, Huntington’s disease, Parkinson’s disease, transmissible encephalopathies, and localized amyloidosis are also diseases associated with deregulation of protein self-assembly and faulty metabolism of protein aggregates. The amyloid aggregates then induce cellular stress and result in cell death and neuronal dysfunction. Furthermore, we are also interested in articles that examine the current challenges and future outlooks of developing therapeutic approaches against amyloid disorders.

Prof. Dr. Chuanhai Cao
Dr. Haifan Wu
Guest Editors

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Keywords

amyloid toxicity
protein aggregation
neurodegeneration
Alzheimer’s disease
Parkinson’s disease

Published Papers (6 papers)

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Research

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25 pages, 3337 KiB

Open AccessArticle

A Combination of Heavy Metals and Intracellular Pathway Modulators Induces Alzheimer Disease-like Pathologies in Organotypic Brain Slices

by Dhwani S. Korde and Christian Humpel

Biomolecules 2024, 14(2), 165; https://doi.org/10.3390/biom14020165 - 30 Jan 2024

Viewed by 1317

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFT). Modelling aspects of AD is challenging due to its complex multifactorial etiology and pathology. The present study aims to establish a cost-effective and rapid method to model the two primary pathologies in organotypic brain slices. Coronal hippocampal brain slices (150 µm) were generated from postnatal (day 8–10) C57BL6 wild-type mice and cultured for 9 weeks. Collagen hydrogels containing either an empty load or a mixture of human Aβ42 and P301S aggregated tau were applied to the slices. The media was further supplemented with various intracellular pathway modulators or heavy metals to augment the appearance of Aβ plaques and tau NFTs, as assessed by immunohistochemistry. Immunoreactivity for Aβ and tau was significantly increased in the ventral areas in slices with a mixture of human Aβ42 and P301S aggregated tau compared to slices with empty hydrogels. Aβ plaque- and tau NFT-like pathologies could be induced independently in slices. Heavy metals (aluminum, lead, cadmium) potently augmented Aβ plaque-like pathology, which developed intracellularly prior to cell death. Intracellular pathway modulators (scopolamine, wortmannin, MHY1485) significantly boosted tau NFT-like pathologies. A combination of nanomolar concentrations of scopolamine, wortmannin, MHY1485, lead, and cadmium in the media strongly increased Aβ plaque- and tau NFT-like immunoreactivity in ventral areas compared to the slices with non-supplemented media. The results highlight that we could harness the potential of the collagen hydrogel-based spreading of human Aβ42 and P301S aggregated tau, along with pharmacological manipulation, to produce pathologies relevant to AD. The results offer a novel ex vivo organotypic slice model to investigate AD pathologies with potential applications for screening drugs or therapies in the future. Full article

(This article belongs to the Special Issue Role of Amyloid Protein in Neurological Diseases)

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25 pages, 3209 KiB

Open AccessEditor’s ChoiceArticle

Decanoic Acid Rescues Differences in AMPA-Mediated Calcium Rises in Hippocampal CA1 Astrocytes and Neurons in the 5xFAD Mouse Model of Alzheimer’s Disease

by Mina Abghari, Jenny Thythy Cecilia Mai Vu, Ninna Eckberg, Blanca I. Aldana and Kristi A. Kohlmeier

Biomolecules 2023, 13(10), 1461; https://doi.org/10.3390/biom13101461 - 27 Sep 2023

Cited by 1 | Viewed by 1138

Abstract

Alzheimer’s disease (AD), a devastating neurodegenerative disease characterized by cognitive dysfunctions, is associated with high levels of amyloid beta 42 (Aβ₄₂), which is believed to play a role in cellular damage and signaling changes in AD. Decanoic acid has been shown to be therapeutic in AD. Glutamatergic signaling within neurons and astrocytes of the CA1 region of the hippocampus is critical in cognitive processes, and previous work has indicated deficiencies in this signaling in a mouse model of AD. In this study, we investigated glutamate-mediated signaling by evaluating AMPA-mediated calcium rises in female and male CA1 neurons and astrocytes in a mouse model of AD and examined the potential of decanoic acid to normalize this signaling. In brain slices from 5xFAD mice in which there are five mutations leading to increasing levels of Aβ₄₂, AMPA-mediated calcium transients in CA1 neurons and astrocytes were significantly lower than that seen in wildtype controls in both females and males. Interestingly, incubation of 5xFAD slices in decanoic acid restored AMPA-mediated calcium levels in neurons and astrocytes in both females and males to levels indistinguishable from those seen in wildtype, whereas similar exposure to decanoic acid did not result in changes in AMPA-mediated transients in neurons or astrocytes in either sex in the wildtype. Our data indicate that one mechanism by which decanoic acid could improve cognitive functioning is through normalizing AMPA-mediated signaling in CA1 hippocampal cells. Full article

(This article belongs to the Special Issue Role of Amyloid Protein in Neurological Diseases)

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22 pages, 3103 KiB

Open AccessFeature PaperArticle

Different Extracellular β-Amyloid (1-42) Aggregates Differentially Impair Neural Cell Adhesion and Neurite Outgrowth through Differential Induction of Scaffold Palladin

by Tianyu Zhang, Chuli Song, He Li, Yanru Zheng and Yingjiu Zhang

Biomolecules 2022, 12(12), 1808; https://doi.org/10.3390/biom12121808 - 02 Dec 2022

Cited by 3 | Viewed by 1299

Abstract

Extracellular amyloid β-protein (1-42) (Aβ42) aggregates have been recognized as toxic agents for neural cells in vivo and in vitro. The aim of this study was to investigate the cytotoxic effects of extracellular Aβ42 aggregates in soluble (or suspended, SAβ42) and deposited (or attached, DAβ42) forms on cell adhesion/re-adhesion, neurite outgrowth, and intracellular scaffold palladin using the neural cell lines SH-SY5Y and HT22, and to elucidate the potential relevance of these effects. The effect of extracellular Aβ42 on neural cell adhesion was directly associated with their neurotrophic or neurotoxic activity, with SAβ42 aggregates reducing cell adhesion and associated live cell de-adherence more than DAβ42 aggregates, while causing higher mortality. The reduction in cell adhesion due to extracellular Aβ42 aggregates was accompanied by the impairment of neurite outgrowth, both in length and number, and similarly, SAβ42 aggregates impaired the extension of neurites more severely than DAβ42 aggregates. Further, the disparate changes of intracellular palladin induced by SAβ42 and DAβ42 aggregates, respectively, might underlie their aforementioned effects on target cells. Further, the use of anti-oligomeric Aβ42 scFv antibodies revealed that extracellular Aβ42 aggregates, especially large DAβ42 aggregates, had some independent detrimental effects, including physical barrier effects on neural cell adhesion and neuritogenesis in addition to their neurotoxicity, which might be caused by the rigid C-terminal clusters formed between adjacent Aβ42 chains in Aβ42 aggregates. Our findings, concerning how scaffold palladin responds to extracellular Aβ42 aggregates, and is closely connected with declines in cell adhesion and neurite outgrowth, provide new insights into the cytotoxicity of extracellular Aβ42 aggregates in Alzheimer disease. Full article

(This article belongs to the Special Issue Role of Amyloid Protein in Neurological Diseases)

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Review

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12 pages, 1392 KiB

Open AccessReview

Updates on Aβ Processing by Hsp90, BRICHOS, and Newly Reported Distinctive Chaperones

by Mohammed Iqbal, Shea-Lorane Lewis, Shivani Padhye and Umesh Kumar Jinwal

Biomolecules 2024, 14(1), 16; https://doi.org/10.3390/biom14010016 - 22 Dec 2023

Viewed by 1032

Abstract

Alzheimer’s disease (AD) is an extremely devastating neurodegenerative disease, and there is no cure for it. AD is specified as the misfolding and aggregation of amyloid-β protein (Aβ) and abnormalities in hyperphosphorylated tau protein. Current approaches to treat Alzheimer’s disease have had some success in slowing down the disease’s progression. However, attempts to find a cure have been largely unsuccessful, most likely due to the complexity associated with AD pathogenesis. Hence, a shift in focus to better understand the molecular mechanism of Aβ processing and to consider alternative options such as chaperone proteins seems promising. Chaperone proteins act as molecular caretakers to facilitate cellular homeostasis under standard conditions. Chaperone proteins like heat shock proteins (Hsps) serve a pivotal role in correctly folding amyloid peptides, inhibiting mitochondrial dysfunction, and peptide aggregation. For instance, Hsp90 plays a significant role in maintaining cellular homeostasis through its protein folding mechanisms. In this review, we analyze the most recent studies from 2020 to 2023 and provide updates on Aβ regulation by Hsp90, BRICHOS domain chaperone, and distinctive newly reported chaperones. Full article

(This article belongs to the Special Issue Role of Amyloid Protein in Neurological Diseases)

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15 pages, 2396 KiB

Open AccessEditor’s ChoiceReview

Phytochemical Interactions with Calmodulin and Critical Calmodulin Binding Proteins Involved in Amyloidogenesis in Alzheimer’s Disease

by Danton H. O'Day

Biomolecules 2023, 13(4), 678; https://doi.org/10.3390/biom13040678 - 15 Apr 2023

Cited by 1 | Viewed by 1823

Abstract

An increasing number of plant-based herbal treatments, dietary supplements, medical foods and nutraceuticals and their component phytochemicals are used as alternative treatments to prevent or slow the onset and progression of Alzheimer’s disease. Their appeal stems from the fact that no current pharmaceutical or medical treatment can accomplish this. While a handful of pharmaceuticals are approved to treat Alzheimer’s, none has been shown to prevent, significantly slow or stop the disease. As a result, many see the appeal of alternative plant-based treatments as an option. Here, we show that many phytochemicals proposed or used as Alzheimer’s treatments share a common theme: they work via a calmodulin-mediated mode of action. Some phytochemicals bind to and inhibit calmodulin directly while others bind to and regulate calmodulin-binding proteins, including Aβ monomers and BACE1. Phytochemical binding to Aβ monomers can prevent the formation of Aβ oligomers. A limited number of phytochemicals are also known to stimulate calmodulin gene expression. The significance of these interactions to amyloidogenesis in Alzheimer’s disease is reviewed. Full article

(This article belongs to the Special Issue Role of Amyloid Protein in Neurological Diseases)

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13 pages, 692 KiB

Open AccessEditor’s ChoiceReview

The Amyloid Cascade Hypothesis in Alzheimer’s Disease: Should We Change Our Thinking?

by Markku Kurkinen, Michał Fułek, Katarzyna Fułek, Jan Aleksander Beszłej, Donata Kurpas and Jerzy Leszek

Biomolecules 2023, 13(3), 453; https://doi.org/10.3390/biom13030453 - 01 Mar 2023

Cited by 16 | Viewed by 5846

Abstract

Old age increases the risk of Alzheimer’s disease (AD), the most common neurodegenerative disease, a devastating disorder of the human mind and the leading cause of dementia. Worldwide, 50 million people have the disease, and it is estimated that there will be 150 million by 2050. Today, healthcare for AD patients consumes 1% of the global economy. According to the amyloid cascade hypothesis, AD begins in the brain by accumulating and aggregating Aβ peptides and forming β-amyloid fibrils (Aβ42). However, in clinical trials, reducing Aβ peptide production and amyloid formation in the brain did not slow cognitive decline or improve daily life in AD patients. Prevention studies in cognitively unimpaired people at high risk or genetically destined to develop AD also have not slowed cognitive decline. These observations argue against the amyloid hypothesis of AD etiology, its development, and disease mechanisms. Here, we look at other avenues in the research of AD, such as the presenilin hypothesis, synaptic glutamate signaling, and the role of astrocytes and the glutamate transporter EAAT2 in the development of AD. Full article

(This article belongs to the Special Issue Role of Amyloid Protein in Neurological Diseases)

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