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Recent Advances in Understanding and Treating Amyloidosis
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Recent Advances in Understanding and Treating Amyloidosis

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 26048

Special Issue Editor

Dr. Valentina Oliveri

E-Mail Website
Guest Editor
Department of Chemistry, Università degli Studi di Catania, Catania, Italy
Interests: amyloid; quinoline; glycoconjugates; protein aggregation; copper; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Amyloidosis is a hallmark of several neurodegenerative disorders (NDs) that afflict large numbers of the world's population. To date, approximately 50 distinct human pathologies, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), have been related to the accumulation of amyloid deposits that consist of ordered protein assemblies formed by a specific peptide or protein. Several factors appear to affect the fate of the amyloid proteins, including metal transition ions and oxidative stress.

Amyloid-β, α-synuclein, and transactive response DNA-binding protein 43 (TDP43), which are involved in AD, PD, and ALS, possess metal-binding sites that have been linked to their neurotoxicity. The binding with metal ions triggers the formation of toxic oligomers and aggregates but, often, also the production of reactive oxygen species.

Despite numerous efforts to advance our understanding of ND etiology and constant research on effective therapies, our information remains incomplete because many potential mechanisms are implicated in neurodegeneration. This Special Issue aims to highlight recent advances in our understanding of the toxic mechanisms involved in NDs and new therapeutic opportunities to modulate self- and metal-induced amyloid aggregation and toxicity.

We welcome original research papers, review articles, and short communications on recent advances and emerging concepts in amyloid-related research.

Dr. Valentina Oliveri
Guest Editor

Keywords

  • neurodegeneration
  • fibrils
  • copper
  • oligomers
  • zinc
  • aggregation inhibitor

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Published Papers (6 papers)

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Research

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15 pages, 3404 KiB  
Article
New Biotinylated GHK and Related Copper(II) Complex: Antioxidant and Antiglycant Properties In Vitro against Neurodegenerative Disorders
by Rita Tosto, Graziella Vecchio and Francesco Bellia
Molecules 2023, 28(18), 6724; https://doi.org/10.3390/molecules28186724 - 20 Sep 2023
Viewed by 1528
Abstract
Neurodegenerative diseases affect millions of people worldwide. The failure of the enzymatic degradation, the oxidative stress, the dyshomeostasis of metal ions, among many other biochemical events, might trigger the pathological route, but the onset of these pathologies is unknown. Multi-target and multifunctional molecules [...] Read more.
Neurodegenerative diseases affect millions of people worldwide. The failure of the enzymatic degradation, the oxidative stress, the dyshomeostasis of metal ions, among many other biochemical events, might trigger the pathological route, but the onset of these pathologies is unknown. Multi-target and multifunctional molecules could address several biomolecular issues of the pathologies. The tripeptide GHK, a bioactive fragment of several proteins, and the related copper(II) complex have been largely used for many purposes, from cosmetic to therapeutic applications. GHK derivatives were synthesized to increase the peptide stability and improve the target delivery. Herein we report the synthesis of a new biotin–GHK conjugate (BioGHK) through orthogonal reactions. BioGHK is still capable of coordinating copper(II), as observed by spectroscopic and spectrometric measurements. The spectroscopic monitoring of the copper-induced ascorbate oxidation was used to measure the antioxidant activity Cu(II)-BioGHK complex, whereas antiglycant activity of the ligand towards harmful reactive species was investigated using MALDI-TOF. The affinity of BioGHK for streptavidin was evaluated using a spectrophotometric assay and compared to that of biotin. Finally, the antiaggregant activity towards amyloid-β was evaluated using a turn-on fluorescent dye. BioGHK could treat and/or prevent several adverse biochemical reactions that characterize neurodegenerative disorders, such as Alzheimer’s disease. Full article
(This article belongs to the Special Issue Recent Advances in Understanding and Treating Amyloidosis)
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16 pages, 2352 KiB  
Article
Multifunctional Small Molecules as Potential Anti-Alzheimer’s Disease Agents
by Beatrice Bargagna, Lidia Ciccone, Susanna Nencetti, M. Amélia Santos, Sílvia Chaves, Caterina Camodeca and Elisabetta Orlandini
Molecules 2021, 26(19), 6015; https://doi.org/10.3390/molecules26196015 - 3 Oct 2021
Cited by 8 | Viewed by 2717
Abstract
Alzheimer’s disease (AD) is a severe multifactorial neurodegenerative disorder characterized by a progressive loss of neurons in the brain. Despite research efforts, the pathogenesis and mechanism of AD progression are not yet completely understood. There are only a few symptomatic drugs approved for [...] Read more.
Alzheimer’s disease (AD) is a severe multifactorial neurodegenerative disorder characterized by a progressive loss of neurons in the brain. Despite research efforts, the pathogenesis and mechanism of AD progression are not yet completely understood. There are only a few symptomatic drugs approved for the treatment of AD. The multifactorial character of AD suggests that it is important to develop molecules able to target the numerous pathological mechanisms associated with the disease. Thus, in the context of the worldwide recognized interest of multifunctional ligand therapy, we report herein the synthesis, characterization, physicochemical and biological evaluation of a set of five (1a–e) new ferulic acid-based hybrid compounds, namely feroyl-benzyloxyamidic derivatives enclosing different substituent groups, as potential anti-Alzheimer’s disease agents. These hybrids can keep both the radical scavenging activity and metal chelation capacity of the naturally occurring ferulic acid scaffold, presenting also good/mild capacity for inhibition of self-Aβ aggregation and fairly good inhibition of Cu-induced Aβ aggregation. The predicted pharmacokinetic properties point towards good absorption, comparable to known oral drugs. Full article
(This article belongs to the Special Issue Recent Advances in Understanding and Treating Amyloidosis)
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7 pages, 224 KiB  
Communication
Combined Subcutaneous Fat Aspirate and Skin Tru-Cut Biopsy for Amyloid Screening in Patients with Suspected Systemic Amyloidosis
by Charlotte Toftmann Hansen, Hanne E. H. Møller, Aleksandra Maria Rojek, Niels Marcussen, Hans Christian Beck and Niels Abildgaard
Molecules 2021, 26(12), 3649; https://doi.org/10.3390/molecules26123649 - 15 Jun 2021
Cited by 5 | Viewed by 2259
Abstract
Screening for systemic amyloidosis is typically carried out with abdominal fat aspirates with varying reported sensitivities. Fat aspirates are preferred for use in primary screening instead of organ biopsies as they are less invasive and thereby minimize the potential risk of complications. At [...] Read more.
Screening for systemic amyloidosis is typically carried out with abdominal fat aspirates with varying reported sensitivities. Fat aspirates are preferred for use in primary screening instead of organ biopsies as they are less invasive and thereby minimize the potential risk of complications. At Odense Amyloidosis Center, we performed a prospective study on whether the combined use of fat aspirate and tru-cut skin biopsy could increase the diagnostic sensitivity. Both fat aspirates and skin biopsies were screened with Congo Red staining, and positive biopsies were subsequently subtyped using immunoelectron microscopy and mass spectrometry. Seventy-six patients were included. In total, 24 patients had systemic amyloidosis (11 AL, 12 wtATTR, 1 AA), and 6 patients had localized amyloidosis. Combined fat aspirate and skin biopsy were Congo Red-positive in 15 patients (overall sensitivity (OS) 62.5%). Fat aspirates were positive in 14 patients (OS 58.3%), and the skin biopsy was positive in 5 patients (OS 20.8%). In only one patient did the skin biopsy add extra diagnostic information. The sensitivity differed between AL and ATTR amyloidosis—81.8% and 41.7%, respectively. Using skin biopsy as the only screening method is not recommended. Full article
(This article belongs to the Special Issue Recent Advances in Understanding and Treating Amyloidosis)
28 pages, 10594 KiB  
Article
Functional Domains and Evolutionary History of the PMEL and GPNMB Family Proteins
by Paul W. Chrystal, Tim Footz, Elizabeth D. Hodges, Justin A. Jensen, Michael A. Walter and W. Ted Allison
Molecules 2021, 26(12), 3529; https://doi.org/10.3390/molecules26123529 - 9 Jun 2021
Cited by 7 | Viewed by 3519
Abstract
The ancient paralogs premelanosome protein (PMEL) and glycoprotein nonmetastatic melanoma protein B (GPNMB) have independently emerged as intriguing disease loci in recent years. Both proteins possess common functional domains and variants that cause a shared spectrum of overlapping phenotypes [...] Read more.
The ancient paralogs premelanosome protein (PMEL) and glycoprotein nonmetastatic melanoma protein B (GPNMB) have independently emerged as intriguing disease loci in recent years. Both proteins possess common functional domains and variants that cause a shared spectrum of overlapping phenotypes and disease associations: melanin-based pigmentation, cancer, neurodegenerative disease and glaucoma. Surprisingly, these proteins have yet to be shown to physically or genetically interact within the same cellular pathway. This juxtaposition inspired us to compare and contrast this family across a breadth of species to better understand the divergent evolutionary trajectories of two related, but distinct, genes. In this study, we investigated the evolutionary history of PMEL and GPNMB in clade-representative species and identified TMEM130 as the most ancient paralog of the family. By curating the functional domains in each paralog, we identified many commonalities dating back to the emergence of the gene family in basal metazoans. PMEL and GPNMB have gained functional domains since their divergence from TMEM130, including the core amyloid fragment (CAF) that is critical for the amyloid potential of PMEL. Additionally, the PMEL gene has acquired the enigmatic repeat domain (RPT), composed of a variable number of imperfect tandem repeats; this domain acts in an accessory role to control amyloid formation. Our analyses revealed the vast variability in sequence, length and repeat number in homologous RPT domains between craniates, even within the same taxonomic class. We hope that these analyses inspire further investigation into a gene family that is remarkable from the evolutionary, pathological and cell biology perspectives. Full article
(This article belongs to the Special Issue Recent Advances in Understanding and Treating Amyloidosis)
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22 pages, 4838 KiB  
Article
Preferred Endocytosis of Amyloid Precursor Protein from Cholesterol-Enriched Lipid Raft Microdomains
by Yoon Young Cho, Oh-Hoon Kwon and Sungkwon Chung
Molecules 2020, 25(23), 5490; https://doi.org/10.3390/molecules25235490 - 24 Nov 2020
Cited by 23 | Viewed by 3156
Abstract
Amyloid precursor protein (APP) at the plasma membrane is internalized via endocytosis and delivered to endo/lysosomes, where neurotoxic amyloid-β (Aβ) is produced via β-, γ-secretases. Hence, endocytosis plays a key role in the processing of APP and subsequent Aβ generation. β-, γ-secretases as [...] Read more.
Amyloid precursor protein (APP) at the plasma membrane is internalized via endocytosis and delivered to endo/lysosomes, where neurotoxic amyloid-β (Aβ) is produced via β-, γ-secretases. Hence, endocytosis plays a key role in the processing of APP and subsequent Aβ generation. β-, γ-secretases as well as APP are localized in cholesterol-enriched lipid raft microdomains. However, it is still unclear whether lipid rafts are the site where APP undergoes endocytosis and whether cholesterol levels affect this process. In this study, we found that localization of APP in lipid rafts was increased by elevated cholesterol level. We also showed that increasing or decreasing cholesterol levels increased or decreased APP endocytosis, respectively. When we labeled cell surface APP, APP localized in lipid rafts preferentially underwent endocytosis compared to nonraft-localized APP. In addition, APP endocytosis from lipid rafts was regulated by cholesterol levels. Our results demonstrate for the first time that cholesterol levels regulate the localization of APP in lipid rafts affecting raft-dependent APP endocytosis. Thus, regulating the microdomain localization of APP could offer a new therapeutic strategy for Alzheimer’s disease. Full article
(This article belongs to the Special Issue Recent Advances in Understanding and Treating Amyloidosis)
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Review

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12 pages, 1204 KiB  
Review
Amyloidosis in Alzheimer’s Disease: Pathogeny, Etiology, and Related Therapeutic Directions
by Chen Ma, Fenfang Hong and Shulong Yang
Molecules 2022, 27(4), 1210; https://doi.org/10.3390/molecules27041210 - 11 Feb 2022
Cited by 72 | Viewed by 11979
Abstract
The amyloid hypothesis of Alzheimer’s disease has long been the predominant theory, suggesting that Alzheimer’s disease is caused by the accumulation of amyloid beta protein (Aβ) in the brain, leading to neuronal toxicity in the central nervous system (CNS). Because of breakthroughs in [...] Read more.
The amyloid hypothesis of Alzheimer’s disease has long been the predominant theory, suggesting that Alzheimer’s disease is caused by the accumulation of amyloid beta protein (Aβ) in the brain, leading to neuronal toxicity in the central nervous system (CNS). Because of breakthroughs in molecular medicine, the amyloid pathway is thought to be central to the pathophysiology of Alzheimer’s disease (AD). Currently, it is believed that altered biochemistry of the Aβ cycle remains a central biological feature of AD and is a promising target for treatment. This review provides an overview of the process of amyloid formation, explaining the transition from amyloid precursor protein to amyloid beta protein. Moreover, we also reveal the relationship between autophagy, cerebral blood flow, ACHE, expression of LRP1, and amyloidosis. In addition, we discuss the detailed pathogenesis of amyloidosis, including oxidative damage, tau protein, NFTs, and neuronal damage. Finally, we list some ways to treat AD in terms of decreasing the accumulation of Aβ in the brain. Full article
(This article belongs to the Special Issue Recent Advances in Understanding and Treating Amyloidosis)
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