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Amyloids in Neurodegenerative Diseases

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

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 69014

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Prof. Dr. Botond Penke

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Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Dóm Square 8, Hungary
Interests: the pathomechanims of neurodegenerative diseases; Alzheimer’s disease (AD); Parkinson’s disease (PD); formation of neurotoxic β-amyloid (Aβ); intracellular Aβ; interaction with subcellular organelles; heat shock proteins (HSPs) in proteostasis; Sigma-1 receptor in neuroprotection; therapeutic strategies in AD treatment

Special Issue Information

Dear Colleagues,

Several peptides and proteins possess amino acid sequences that are prone to convert from their native physiological conformation into toxic aggregates. Misfolded, pathologically altered proteins (amyloids) form deposits in distinctive regions of the human central nervous system (CNS) in increasingly common neurodegenerative diseases (NDDs), such as Alzheimer’s, Parkinson’s, and prion diseases. In this Special Issue, we describe the formation of amyloids from precursors and their nucleated polymerization. The mechanisms of generating cellular dysfunction and cell-to-cell transmission of amyloids are also shown. We summarize genetic factors and mutations that determine amyloid formation and toxicity. We show the activity of the complex proteostasis network for degrading and clearing amyloids in the CNS. This Special Issue provides a forum for the dissemination of the most recent results on the formation and structure of different amyloid assemblies and their role in the pathomechanisms of NDDs. We also summarize recent developments of novel therapeutic strategies for combatting currently incurable NDDs.

Prof. Dr. Botond Penke
Guest Editor

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Keywords

APP processing and Aβ formation
Folding and misfolding: methods for studying amyloid structures, and aggregation
Nucleated polymerization of Aβ to oligomers, protofibrils and fibrils
Tau protein, aggregation to neurofibrillary tangles
Aβ-tau interactions
Aβ and tau interaction with proteins, subcellular organelles, and glial cells
signalization disturbances
Aβ and tau interactions with membrane lipids
cell-to-cell transmission
α-Synuclein, huntingtin, and prion protein
Proteostasis pathways: amyloid degradation and clearance
Drug development against amyloids such as Aβ and tau

Published Papers (13 papers)

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Research

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11 pages, 1596 KiB

Open AccessArticle

Fluorescence-Labeled Amyloid Beta Monomer: A Molecular Dynamical Study

by János Gera and Gábor Paragi

Molecules 2020, 25(15), 3524; https://doi.org/10.3390/molecules25153524 - 1 Aug 2020

Cited by 2 | Viewed by 2699

Abstract

The aggregation process of the Amyloidβ (Aβ) peptide is one of the central questions in Alzheimers’s research. Fluorescence-labeled single-molecule detection is a novel technique concerning the early stage investigation of Aβ aggregation, where the labeling dyes are covalently bound to the Aβ monomer. As the influence of the dye on the conformational space of the Aβ monomer can be significant, its effect on the seeding process is an open question. The applied fluorescent molecule continuously switches between an active (ON) and an inactive (OFF) state, where the latter supports an extra rotational restriction at many commercially available dyes. However, only a few theoretical studies simulated the Aβ monomer in the presence of a dye and none of them considered the difference between the ON and the OFF states. Therefore, we examined the impact of a selected fluorescence dye (Alexa 568) on the conformational space of the monomeric Aβ(1–42) peptide in its ON and OFF state by replica exchange molecular dynamic simulations. Investigations on secondary structure elements as well as dye-peptide contact analysis for the monomers are presented. Experimental and theoretical NMR shifts were contrasted to qualify the calculation protocol and theoretical values of the labeled and the non-labeled peptide were also compared. We found that the first five residues have higher helical propensity in the presence of the dye, and electrostatic properties could strongly affect the connection between the dye and the peptide parts. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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17 pages, 2996 KiB

Open AccessArticle

One- and Two-Electron Oxidations of β-Amyloid_25-35 by Carbonate Radical Anion (CO₃^•−) and Peroxymonocarbonate (HCO₄⁻): Role of Sulfur in Radical Reactions and Peptide Aggregation

by Antonio Francioso, Alessia Baseggio Conrado, Carla Blarzino, Cesira Foppoli, Elita Montanari, Simone Dinarelli, Alessandra Giorgi, Luciana Mosca and Mario Fontana

Molecules 2020, 25(4), 961; https://doi.org/10.3390/molecules25040961 - 20 Feb 2020

Cited by 12 | Viewed by 3781

Abstract

The β-amyloid (Aβ) peptide plays a key role in the pathogenesis of Alzheimer’s disease. The methionine (Met) residue at position 35 in Aβ C-terminal domain is critical for neurotoxicity, aggregation, and free radical formation initiated by the peptide. The role of Met in modulating toxicological properties of Aβ most likely involves an oxidative event at the sulfur atom. We therefore investigated the one- or two-electron oxidation of the Met residue of Aβ_25-35 fragment and the effect of such oxidation on the behavior of the peptide. Bicarbonate promotes two-electron oxidations mediated by hydrogen peroxide after generation of peroxymonocarbonate (HCO₄⁻, PMC). The bicarbonate/carbon dioxide pair stimulates one-electron oxidations mediated by carbonate radical anion (CO₃^•−). PMC efficiently oxidizes thioether sulfur of the Met residue to sulfoxide. Interestingly, such oxidation hampers the tendency of Aβ to aggregate. Conversely, CO₃^•− causes the one-electron oxidation of methionine residue to sulfur radical cation (MetS^•+). The formation of this transient reactive intermediate during Aβ oxidation may play an important role in the process underlying amyloid neurotoxicity and free radical generation. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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11 pages, 2110 KiB

Open AccessCommunication

Amyloid-Beta_1-42 -Induced Increase in GABAergic Tonic Conductance in Mouse Hippocampal CA1 Pyramidal Cells

by Beatriz Calvo-Flores Guzmán, SooHyun Kim, Bhavya Chawdhary, Katie Peppercorn, Warren P Tate, Henry J Waldvogel, Richard LM Faull, Johanna Montgomery and Andrea Kwakowsky

Molecules 2020, 25(3), 693; https://doi.org/10.3390/molecules25030693 - 6 Feb 2020

Cited by 15 | Viewed by 3421

Abstract

Alzheimer’s disease (AD) is a complex and chronic neurodegenerative disorder that involves a progressive and severe decline in cognition and memory. During the last few decades a considerable amount of research has been done in order to better understand tau-pathology, inflammatory activity and neuronal synapse loss in AD, all of them contributing to cognitive decline. Early hippocampal network dysfunction is one of the main factors associated with cognitive decline in AD. Much has been published about amyloid-beta_1-42 (Aβ_1-42)-mediated excitotoxicity in AD. However, increasing evidence demonstrates that the remodeling of the inhibitory gamma-aminobutyric acid (GABAergic) system contributes to the excitatory/inhibitory (E/I) disruption in the AD hippocampus, but the underlying mechanisms are not well understood. In the present study, we show that hippocampal injection of Aβ_1-42 is sufficient to induce cognitive deficits 7 days post-injection. We demonstrate using in vitro whole-cell patch-clamping an increased inhibitory GABAergic tonic conductance mediated by extrasynaptic type A GABA receptors (GABA_ARs), recorded in the CA1 region of the mouse hippocampus following Aβ_1-42 micro injection. Such alterations in GABA neurotransmission and/or inhibitory GABA_ARs could have a significant impact on both hippocampal structure and function, causing E/I balance disruption and potentially contributing to cognitive deficits in AD. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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16 pages, 2102 KiB

Open AccessArticle

Substrate-Specific Activation of α-Secretase by 7-Deoxy-Trans-Dihydronarciclasine Increases Non-Amyloidogenic Processing of β-Amyloid Protein Precursor

by Yoon Sun Chun, Yoon Young Cho, Oh Hoon Kwon, Dong Zhao, Hyun Ok Yang and Sungkwon Chung

Molecules 2020, 25(3), 646; https://doi.org/10.3390/molecules25030646 - 3 Feb 2020

Cited by 6 | Viewed by 2818

Abstract

Accumulation of β-amyloid (Aβ) in the brain has been implicated in the pathology of Alzheimer’s disease (AD). Aβ is produced from the Aβ precursor protein (APP) through the amyloidogenic pathway by β-, and γ-secretase. Alternatively, APP can be cleaved by α-, and γ-secretase, precluding the production of Aβ. Thus, stimulating α-secretase mediated APP processing is considered a therapeutic option not only for decreasing Aβ production but for increasing neuroprotective sAPPα. We have previously reported that 7-deoxy-trans-dihydronarciclasine (E144), the active component of Lycoris chejuensis, decreases Aβ production by attenuating APP level, and retarding APP maturation. It can also improve cognitive function in the AD model mouse. In this study, we further analyzed the activating effect of E144 on α-secretase. Treatment of E144 increased sAPPα, but decreased β-secretase products from HeLa cells stably transfected with APP. E144 directly activated ADAM10 and ADAM17 in a substrate-specific manner both in cell-based and in cell-free assays. The Lineweaver–Burk plot analysis revealed that E144 enhanced the affinities of A Disintegrin and Metalloproteinases (ADAMs) towards the substrate. Consistent with this result, immunoprecipitation analysis showed that interactions of APP with ADAM10 and ADAM17 were increased by E144. Our results indicate that E144 might be a novel agent for AD treatment as a substrate-specific activator of α-secretase. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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22 pages, 11701 KiB

Open AccessArticle

Alternative Structures of α-Synuclein

by Dawid Dułak, Małgorzata Gadzała, Mateusz Banach, Leszek Konieczny and Irena Roterman

Molecules 2020, 25(3), 600; https://doi.org/10.3390/molecules25030600 - 30 Jan 2020

Cited by 9 | Viewed by 2885

Abstract

The object of our analysis is the structure of alpha-synuclein (ASyn), which, under in vivo conditions, associates with presynaptic vesicles. Misfolding of ASyn is known to be implicated in Parkinson’s disease. The availability of structural information for both the micelle-bound and amyloid form of ASyn enables us to speculate on the specific mechanism of amyloid transformation. This analysis is all the more interesting given the fact that—Unlike in Aβ(1–42) amyloids—only the central fragment (30–100) of ASyn has a fibrillar structure, whereas, its N- and C-terminal fragments (1–30 and 100–140, respectively) are described as random coils. Our work addresses the following question: Can the ASyn chain—as well as the aforementioned individual fragments—adopt globular conformations? In order to provide an answer, we subjected the corresponding sequences to simulations carried out using Robetta and I-Tasser, both of which are regarded as accurate protein structure predictors. In addition, we also applied the fuzzy oil drop (FOD) model, which, in addition to optimizing the protein’s internal free energy, acknowledges the presence of an external force field contributed by the aqueous solvent. This field directs hydrophobic residues to congregate near the center of the protein body while exposing hydrophilic residues on its surface. Comparative analysis of the obtained models suggests that fragments which do not participate in forming the amyloid fibril (i.e., 1–30 and 100–140) can indeed attain globular conformations. We also explain the influence of mutations observed in vivo upon the susceptibility of ASyn to undergo amyloid transformation. In particular, the 30–100 fragment (which adopts a fibrillar structure in PDB) is not predicted to produce a centralized hydrophobic core by any of the applied toolkits (Robetta, I-Tasser, and FOD). This means that in order to minimize the entropically disadvantageous contact between hydrophobic residues and the polar solvent, ASyn adopts the form of a ribbonlike micelle (rather than a spherical one). In other words, the ribbonlike micelle represents a synergy between the conformational preferences of the protein chain and the influence of its environment. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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18 pages, 3609 KiB

Open AccessArticle

Amyloid-Beta Peptides Trigger Aggregation of Alpha-Synuclein In Vitro

by Janett Köppen, Anja Schulze, Lisa Machner, Michael Wermann, Rico Eichentopf, Max Guthardt, Angelika Hähnel, Jessica Klehm, Marie-Christin Kriegeskorte, Maike Hartlage-Rübsamen, Markus Morawski, Stephan von Hörsten, Hans-Ulrich Demuth, Steffen Roßner and Stephan Schilling

Molecules 2020, 25(3), 580; https://doi.org/10.3390/molecules25030580 - 29 Jan 2020

Cited by 52 | Viewed by 6958

Abstract

Alzheimer’s disease (AD) and Parkinson’s disease (PD), including dementia with Lewy bodies (DLB), account for the majority of dementia cases worldwide. Interestingly, a significant number of patients have clinical and neuropathological features of both AD and PD, i.e., the presence of amyloid deposits and Lewy bodies in the neocortex. The identification of α-synuclein peptides in amyloid plaques in DLB brain led to the hypothesis that both peptides mutually interact with each other to facilitate neurodegeneration. In this article, we report the influence of Aβ(1–42) and pGlu-Aβ(3–42) on the aggregation of α-synuclein in vitro. The aggregation of human recombinant α-synuclein was investigated using thioflavin-T fluorescence assay. Fibrils were investigated by means of antibody conjugated immunogold followed by transmission electron microscopy (TEM). Our data demonstrate a significantly increased aggregation propensity of α-synuclein in the presence of minor concentrations of Aβ(1–42) and pGlu-Aβ(3–42) for the first time, but without effect on toxicity on mouse primary neurons. The analysis of the composition of the fibrils by TEM combined with immunogold labeling of the peptides revealed an interaction of α-synuclein and Aβ in vitro, leading to an accelerated fibril formation. The analysis of kinetic data suggests that significantly enhanced nucleus formation accounts for this effect. Additionally, co-occurrence of α-synuclein and Aβ and pGlu-Aβ, respectively, under pathological conditions was confirmed in vivo by double immunofluorescent labelings in brains of aged transgenic mice with amyloid pathology. These observations imply a cross-talk of the amyloid peptides α-synuclein and Aβ species in neurodegeneration. Such effects might be responsible for the co-occurrence of Lewy bodies and plaques in many dementia cases. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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7 pages, 1260 KiB

Open AccessArticle

Postmortem Quantitative Analysis of Prion Seeding Activity in the Digestive System

by Katsuya Satoh, Takayuki Fuse, Toshiaki Nonaka, Trong Dong, Masaki Takao, Takehiro Nakagaki, Daisuke Ishibashi, Yuzuru Taguchi, Ban Mihara, Yasushi Iwasaki, Mari Yoshida and Noriyuki Nishida

Molecules 2019, 24(24), 4601; https://doi.org/10.3390/molecules24244601 - 16 Dec 2019

Cited by 11 | Viewed by 2971

Abstract

Human prion diseases are neurodegenerative disorders caused by prion protein. Although infectivity was historically detected only in the central nervous system and lymphoreticular tissues of patients with sporadic Creutzfeldt-Jakob disease, recent reports suggest that the seeding activity of Creutzfeldt-Jakob disease prions accumulates in various non-neuronal organs including the liver, kidney, and skin. Therefore, we reanalyzed autopsy samples collected from patients with sporadic and genetic human prion diseases and found that seeding activity exists in almost all digestive organs. Unexpectedly, activity in the esophagus reached a level of prion seeding activity close to that in the central nervous system in some CJD patients, indicating that the safety of endoscopic examinations should be reconsidered. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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Review

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29 pages, 3301 KiB

Open AccessReview

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

by Botond Penke, Mária Szűcs and Ferenc Bogár

Molecules 2020, 25(7), 1659; https://doi.org/10.3390/molecules25071659 - 3 Apr 2020

Cited by 59 | Viewed by 11812

Abstract

The structural polymorphism and the physiological and pathophysiological roles of two important proteins, β-amyloid (Aβ) and tau, that play a key role in Alzheimer’s disease (AD) are reviewed. Recent results demonstrate that monomeric Aβ has important physiological functions. Toxic oligomeric Aβ assemblies (AβOs) may play a decisive role in AD pathogenesis. The polymorph fibrillar Aβ (fAβ) form has a very ordered cross-β structure and is assumed to be non-toxic. Tau monomers also have several important physiological actions; however, their oligomerization leads to toxic oligomers (TauOs). Further polymerization results in probably non-toxic fibrillar structures, among others neurofibrillary tangles (NFTs). Their structure was determined by cryo-electron microscopy at atomic level. Both AβOs and TauOs may initiate neurodegenerative processes, and their interactions and crosstalk determine the pathophysiological changes in AD. TauOs (perhaps also AβO) have prionoid character, and they may be responsible for cell-to-cell spreading of the disease. Both extra- and intracellular AβOs and TauOs (and not the previously hypothesized amyloid plaques and NFTs) may represent the novel targets of AD drug research. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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20 pages, 3714 KiB

Open AccessReview

Amyloids: Regulators of Metal Homeostasis in the Synapse

by Masahiro Kawahara, Midori Kato-Negishi and Ken-ichiro Tanaka

Molecules 2020, 25(6), 1441; https://doi.org/10.3390/molecules25061441 - 23 Mar 2020

Cited by 22 | Viewed by 3793

Abstract

Conformational changes in amyloidogenic proteins, such as β-amyloid protein, prion proteins, and α-synuclein, play a critical role in the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease, prion disease, and Lewy body disease. The disease-associated proteins possess several common characteristics, including the ability to form amyloid oligomers with β-pleated sheet structure, as well as cytotoxicity, although they differ in amino acid sequence. Interestingly, these amyloidogenic proteins all possess the ability to bind trace metals, can regulate metal homeostasis, and are co-localized at the synapse, where metals are abundantly present. In this review, we discuss the physiological roles of these amyloidogenic proteins in metal homeostasis, and we propose hypothetical models of their pathogenetic role in the neurodegenerative process as the loss of normal metal regulatory functions of amyloidogenic proteins. Notably, these amyloidogenic proteins have the capacity to form Ca²⁺-permeable pores in membranes, suggestive of a toxic gain of function. Therefore, we focus on their potential role in the disruption of Ca²⁺ homeostasis in amyloid-associated neurodegenerative diseases. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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30 pages, 2725 KiB

Open AccessReview

Structure and Aggregation Mechanisms in Amyloids

by Zaida L. Almeida and Rui M. M. Brito

Molecules 2020, 25(5), 1195; https://doi.org/10.3390/molecules25051195 - 6 Mar 2020

Cited by 105 | Viewed by 15465

Abstract

The aggregation of a polypeptide chain into amyloid fibrils and their accumulation and deposition into insoluble plaques and intracellular inclusions is the hallmark of several misfolding diseases known as amyloidoses. Alzheimer′s, Parkinson′s and Huntington’s diseases are some of the approximately 50 amyloid diseases described to date. The identification and characterization of the molecular species critical for amyloid formation and disease development have been the focus of intense scrutiny. Methods such as X-ray and electron diffraction, solid-state nuclear magnetic resonance spectroscopy (ssNMR) and cryo-electron microscopy (cryo-EM) have been extensively used and they have contributed to shed a new light onto the structure of amyloid, revealing a multiplicity of polymorphic structures that generally fit the cross-β amyloid motif. The development of rational therapeutic approaches against these debilitating and increasingly frequent misfolding diseases requires a thorough understanding of the molecular mechanisms underlying the amyloid cascade. Here, we review the current knowledge on amyloid fibril formation for several proteins and peptides from a kinetic and thermodynamic point of view, the structure of the molecular species involved in the amyloidogenic process, and the origin of their cytotoxicity. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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14 pages, 921 KiB

Open AccessReview

Amyloidogenic Peptides in Human Neuro-Degenerative Diseases and in Microorganisms: A Sorrow Shared Is a Sorrow Halved?

by Kristina Endres

Molecules 2020, 25(4), 925; https://doi.org/10.3390/molecules25040925 - 19 Feb 2020

Cited by 7 | Viewed by 2942

Abstract

The term “amyloid” refers to proteinaceous deposits of peptides that might be generated from larger precursor proteins e.g., by proteolysis. Common to these peptides is a stable cross-β dominated secondary structure which allows self-assembly, leading to insoluble oligomers and lastly to fibrils. These highly ordered protein aggregates have been, for a long time, mainly associated with human neurodegenerative diseases such as Alzheimer’s disease (Amyloid-β peptides). However, they also exert physiological functions such as in release of deposited hormones in human beings. In the light of the rediscovery of our microbial commensals as important companions in health and disease, the fact that microbes also possess amyloidogenic peptides is intriguing. Transmission of amyloids by iatrogenic means or by consumption of contaminated meat from diseased animals is a well-known fact. What if also our microbial commensals might drive human amyloidosis or suffer from our aggregated amyloids? Moreover, as the microbial amyloids are evolutionarily older, we might learn from these organisms how to cope with the sword of Damocles forged of endogenous, potentially toxic peptides. This review summarizes knowledge about the interplay between human amyloids involved in neurodegenerative diseases and microbial amyloids. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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16 pages, 4320 KiB

Open AccessReview

The Amyloid as a Ribbon-Like Micelle in Contrast to Spherical Micelles Represented by Globular Proteins

by Mateusz Banach, Leszek Konieczny and Irena Roterman

Molecules 2019, 24(23), 4395; https://doi.org/10.3390/molecules24234395 - 3 Dec 2019

Cited by 14 | Viewed by 3199

Abstract

Selected amyloid structures available in the Protein Data Bank have been subjected to a comparative analysis. Classification is based on the distribution of hydrophobicity in amyloids that differ with respect to sequence, chain length, the distribution of beta folds, protofibril structure, and the arrangement of protofibrils in each superfibril. The study set includes the following amyloids: Aβ (1–42), which is listed as Aβ (15–40) and carries the D23N mutation, and Aβ (11–42) and Aβ (1–40), both of which carry the E22Δ mutation, tau amyloid, and α-synuclein. Based on the fuzzy oil drop model (FOD), we determined that, despite their conformational diversity, all presented amyloids adopt a similar structural pattern that can be described as a ribbon-like micelle. The same model, when applied to globular proteins, results in structures referred to as “globular micelles,” emerging as a result of interactions between the proteins’ constituent residues and the aqueous solvent. Due to their composition, amyloids are unable to attain entropically favorable globular forms and instead attempt to limit contact between hydrophobic residues and water by producing elongated structures. Such structures typically contain quasi hydrophobic cores that stretch along the fibril’s long axis. Similar properties are commonly found in ribbon-like micelles, with alternating bands of high and low hydrophobicity emerging as the fibrils increase in length. Thus, while globular proteins are generally consistent with a 3D Gaussian distribution of hydrophobicity, the distribution instead conforms to a 2D Gaussian distribution in amyloid fibrils. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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20 pages, 1295 KiB

Open AccessReview

The Nervous System Relevance of the Calcium Sensing Receptor in Health and Disease

by Maria Lo Giudice, Balázs Mihalik, András Dinnyés and Julianna Kobolák

Molecules 2019, 24(14), 2546; https://doi.org/10.3390/molecules24142546 - 12 Jul 2019

Cited by 26 | Viewed by 5500

Abstract

The calcium sensing receptor (CaSR) was first identified in parathyroid glands, and its primary role in controlling systemic calcium homeostasis by the regulation of parathyroid hormone (PTH) secretion has been extensively described in literature. Additionally, the receptor has also been investigated in cells and tissues not directly involved in calcium homeostasis, e.g., the nervous system (NS), where it plays crucial roles in early neural development for the differentiation of neurons and glial cells, as well as in the adult nervous system for synaptic transmission and plasticity. Advances in the knowledge of the CaSR’s function in such physiological processes have encouraged researchers to further broaden the receptor’s investigation in the neuro-pathological conditions of the NS. Interestingly, pre-clinical data suggest that receptor inhibition by calcilytics might be effective in counteracting the pathomechanism underlying Alzheimer’s disease and ischemia, while a CaSR positive modulation with calcimimetics has been proposed as a potential approach for treating neuroblastoma. Importantly, such promising findings led to the repurposing of CaSR modulators as novel pharmacological alternatives for these disorders. Therefore, the aim of this review article is to critically appraise evidence which, so far, has been yielded from the investigation of the role of the CaSR in physiology of the nervous system and to focus on the most recent emerging concepts which have reported the receptor as a therapeutic target for neurodegeneration and neuroblastic tumors. Full article

(This article belongs to the Special Issue Amyloids in Neurodegenerative Diseases)

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