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The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis...
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The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (30 August 2021) | Viewed by 81724

Special Issue Editors

Dr. Nadia D'Ambrosi

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Guest Editor
Department of Biology, University of Rome Tor Vergata, Rome, Italy
Interests: microglia; astrocytes; neuroinflammation; amyotrophic lateral sclerosis (ALS); neurodegenerative diseases; non-cell autonomous neurodegeneration; mutant SOD1; FUS; fibro-glial scar; extracellular matrix; Friedreich's ataxia; RNA splicing
Special Issues, Collections and Topics in MDPI journals
Dr. Savina Apolloni

E-Mail Website
Guest Editor
Department of Biology, Tor Vergata University of Rome, 00133 Rome, Italy
Interests: molecular mechanisms of neurodegeneration; amyotrophic lateral sclerosis; neuroinflammation; microglia; fibrosis; astrocytes; animal models of neurodegenerative diseases; purinergic signaling; histaminergic signaling; neuropharmacology
Special Issues, Collections and Topics in MDPI journals
Dr. Mauro Cozzolino

E-Mail Website
Guest Editor
Institute of Translational Pharmacology, National Research Council, Rome, Italy
Interests: neurodegeneration; motor neuron diseases; amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA); protein aggregation; RNA metabolism; RNA splicing; stress response

Special Issue Information

Dear Colleagues,

Neuron loss occurring in neurodegenerative diseases represents just the tip of the iceberg in a series of events where cells, other than neurons, actively contribute to the pathogenic mechanisms, establishing harmful non-cell autonomous processes. In this aspect, amyotrophic lateral sclerosis is paradigmatic of the most common neurodegenerative disorders, since motor neuron demise, the major event characterizing the disease, is accompanied by the activation of astrocytic and microglial cells activation, oligodendrogliopathy, blood brain barrier permeabilization, T cells, macrophages and mast cells infiltration, neuromuscular junction dismantling, muscle alterations and dyslipidemia. Furthermore, the disease can involve the impairment of neurons other than the motor ones, such as those of the frontotemporal lobe. Several of the aforementioned mechanisms are activated before overt symptoms and detectable motor neuron loss, suggesting an implication in early events that can be considered causative of the disease. Importantly, it is now clear that at least some of these events commonly occur in a number of other neurodegenerative conditions.

The aim of this Special Issue is to highlight the role of non-neuronal cells in the onset and progression of different neurodegenerative diseases, such as Parkinson's, Alzheimer's and dementias, Huntington's, spinocerebellar ataxias, spinal muscular atrophy and prion diseases. In addition, we would like to emphasize how intervention in non-neuronal targets may hamper disease pathological features, representing potential mainstream or complementary therapies to contrast such complex pathologies. Within this Special Issue, we welcome original research and review articles to provide an up-to-date and stimulating discussion on these topics.

Prof. Nadia D'Ambrosi
Dr. Savina Apolloni
Dr. Mauro Cozzolino
Guest Editors

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Keywords

  • glia
  • macrophages
  • T cells
  • pericytes
  • muscles
  • adipose tissue
  • Parkinson's disease
  • Alzheimer's disease
  • motor neuron diseases
  • poly-glutamine disorders

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Published Papers (14 papers)

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Editorial

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3 pages, 190 KiB  
Editorial
The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges
by Nadia D’Ambrosi, Mauro Cozzolino and Savina Apolloni
Cells 2022, 11(2), 193; https://doi.org/10.3390/cells11020193 - 6 Jan 2022
Cited by 6 | Viewed by 1777
Abstract
Neuron loss occurring in neurodegenerative diseases represents just the final step in a series of events involving several cell types, other than neurons, that actively contribute to the overall pathogenic mechanisms by establishing harmful non-cell autonomous effects [...] Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)

Research

Jump to: Editorial, Review

26 pages, 3045 KiB  
Article
Differences in Immune-Related Genes Underlie Temporal and Regional Pathological Progression in 3xTg-AD Mice
by Adelaide Fernandes, Cláudia Caldeira, Carolina Cunha, Elisabete Ferreiro, Ana Rita Vaz and Dora Brites
Cells 2022, 11(1), 137; https://doi.org/10.3390/cells11010137 - 1 Jan 2022
Cited by 9 | Viewed by 3539
Abstract
The prevalence of Alzheimer’s disease (AD), the most common cause of age-associated dementia, is estimated to increase over the next decades. Evidence suggests neuro-immune signaling deregulation and risk genes beyond the amyloid-β (Aβ) deposition in AD pathology. We examined the temporal profile of [...] Read more.
The prevalence of Alzheimer’s disease (AD), the most common cause of age-associated dementia, is estimated to increase over the next decades. Evidence suggests neuro-immune signaling deregulation and risk genes beyond the amyloid-β (Aβ) deposition in AD pathology. We examined the temporal profile of inflammatory mediators and microglia deactivation/activation in the brain cortex and hippocampus of 3xTg-AD mice at 3- and 9-month-old. We found upregulated APP processing, decreased expression of CD11b, CX3CR1, MFG-E8, TNF-α, IL-1β, MHC-II and C/EBP-α and increased miR-146a in both brain regions in 3-month-old 3xTG-AD mice, suggestive of a restrictive regulation. Enhanced TNF-α, IL-1β, IL-6, iNOS, SOCS1 and Arginase 1 were only present in the hippocampus of 9-month-old animals, though elevation of HMGB1 and reduction of miR-146a and miR-124 were common features in the hippocampus and cortex regions. miR-155 increased early in the cortex and later in both regions, supporting its potential as a biomarker. Candidate downregulated target genes by cortical miR-155 included Foxo3, Runx2 and CEBPβ at 3 months and Foxo3, Runx2 and Socs1 at 9 months, which are implicated in cell survival, but also in Aβ pathology and microglia/astrocyte dysfunction. Data provide new insights across AD state trajectory, with divergent microglia phenotypes and inflammatory-associated features, and identify critical targets for drug discovery and combinatorial therapies. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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15 pages, 4632 KiB  
Article
Modulation of Inflammasome and Pyroptosis by Olaparib, a PARP-1 Inhibitor, in the R6/2 Mouse Model of Huntington’s Disease
by Emanuela Paldino, Vincenza D’Angelo, Daunia Laurenti, Cecilia Angeloni, Giuseppe Sancesario and Francesca R. Fusco
Cells 2020, 9(10), 2286; https://doi.org/10.3390/cells9102286 - 13 Oct 2020
Cited by 36 | Viewed by 3126
Abstract
Pyroptosis is a type of cell death that is caspase-1 (Casp-1) dependent, which leads to a rapid cell lysis, and it is linked to the inflammasome. We recently showed that pyroptotic cell death occurs in Huntington’s disease (HD). Moreover, we previously described the [...] Read more.
Pyroptosis is a type of cell death that is caspase-1 (Casp-1) dependent, which leads to a rapid cell lysis, and it is linked to the inflammasome. We recently showed that pyroptotic cell death occurs in Huntington’s disease (HD). Moreover, we previously described the beneficial effects of a PARP-1 inhibitor in HD. In this study, we investigated the neuroprotective effect of Olaparib, an inhibitor of PARP-1, in the mouse model of Huntington’s disease. R6/2 mice were administered Olaparib or vehicle from pre-symptomatic to late stages. Behavioral studies were performed to investigate clinical effects of the compound. Immunohistochemical and Western blotting studies were performed to evaluate neuroprotection and the impact of the compound on the pathway of neuronal death in the HD mice. Our results indicate that Olaparib administration starting from the pre-symptomatic stage of the neurodegenerative disease increased survival, ameliorated the neurological deficits, and improved clinical outcomes in neurobehavioral tests mainly by modulating the inflammasome activation. These results suggest that Olaparib, a commercially available drug already in use as an anti-neoplastic compound, exerts a neuroprotective effect and could be a useful pharmaceutical agent for Huntington’s disease therapy. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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12 pages, 1677 KiB  
Article
Creatine Kinase and Progression Rate in Amyotrophic Lateral Sclerosis
by Marco Ceccanti, Valeria Pozzilli, Chiara Cambieri, Laura Libonati, Emanuela Onesti, Vittorio Frasca, Ilenia Fiorini, Antonio Petrucci, Matteo Garibaldi, Eleonora Palma, Caterina Bendotti, Paola Fabbrizio, Maria Chiara Trolese, Giovanni Nardo and Maurizio Inghilleri
Cells 2020, 9(5), 1174; https://doi.org/10.3390/cells9051174 - 8 May 2020
Cited by 22 | Viewed by 5571
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no recognized clinical prognostic factor. Creatinine kinase (CK) increase in these patients is already described with conflicting results on prognosis and survival. In 126 ALS patients who were fast or slow disease progressors, CK [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no recognized clinical prognostic factor. Creatinine kinase (CK) increase in these patients is already described with conflicting results on prognosis and survival. In 126 ALS patients who were fast or slow disease progressors, CK levels were assayed for 16 months every 4 months in an observational case-control cohort study with prospective data collection conducted in Italy. CK was also measured at baseline in 88 CIDP patients with secondary axonal damage and in two mouse strains (129SvHSD and C57-BL) carrying the same SOD1G93A transgene expression but showing a fast (129Sv-SOD1G93A) and slow (C57-SOD1G93A) ALS progression rate. Higher CK was found in ALS slow progressors compared to fast progressors in T1, T2, T3, and T4, with a correlation with Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores. Higher CK was found in spinal compared to bulbar-onset patients. Transgenic and non-transgenic C57BL mice showed higher CK levels compared to 129SvHSD strain. At baseline mean CK was higher in ALS compared to CIDP. CK can predict the disease progression, with slow progressors associated with higher levels and fast progressors to lower levels, in both ALS patients and mice. CK is higher in ALS patients compared to patients with CIDP with secondary axonal damage; the higher levels of CK in slow progressors patients, but also in C57BL transgenic and non-transgenic mice designs CK as a predisposing factor for disease rate progression. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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Review

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18 pages, 2300 KiB  
Review
Dysfunction of RNA/RNA-Binding Proteins in ALS Astrocytes and Microglia
by Simona Rossi and Mauro Cozzolino
Cells 2021, 10(11), 3005; https://doi.org/10.3390/cells10113005 - 3 Nov 2021
Cited by 6 | Viewed by 4198
Abstract
Amyotrophic Lateral Sclerosis is a neurological disease that primarily affects motor neurons in the cortex, brainstem, and spinal cord. The process that leads to motor neuron degeneration is strongly influenced by non-motor neuronal events that occur in a variety of cell types. Among [...] Read more.
Amyotrophic Lateral Sclerosis is a neurological disease that primarily affects motor neurons in the cortex, brainstem, and spinal cord. The process that leads to motor neuron degeneration is strongly influenced by non-motor neuronal events that occur in a variety of cell types. Among these, neuroinflammatory processes mediated by activated astrocytes and microglia play a relevant role. In recent years, it has become clear that dysregulation of essential steps of RNA metabolism, as a consequence of alterations in RNA-binding proteins (RBPs), is a central event in the degeneration of motor neurons. Yet, a causal link between dysfunctional RNA metabolism and the neuroinflammatory processes mediated by astrocytes and microglia in ALS has been poorly defined. In this review, we will discuss the available evidence showing that RBPs and associated RNA processing are affected in ALS astrocytes and microglia, and the possible mechanisms involved in these events. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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19 pages, 2144 KiB  
Review
Alzheimer’s Disease, Sleep Disordered Breathing, and Microglia: Puzzling out a Common Link
by Tyler K. Ulland, Andrea C. Ewald, Andrew O. Knutson, Kaitlyn M. Marino, Stephanie M. C. Smith and Jyoti J. Watters
Cells 2021, 10(11), 2907; https://doi.org/10.3390/cells10112907 - 27 Oct 2021
Cited by 14 | Viewed by 4329
Abstract
Sleep Disordered Breathing (SDB) and Alzheimer’s Disease (AD) are strongly associated clinically, but it is unknown if they are mechanistically associated. Here, we review data covering both the cellular and molecular responses in SDB and AD with an emphasis on the overlapping neuroimmune [...] Read more.
Sleep Disordered Breathing (SDB) and Alzheimer’s Disease (AD) are strongly associated clinically, but it is unknown if they are mechanistically associated. Here, we review data covering both the cellular and molecular responses in SDB and AD with an emphasis on the overlapping neuroimmune responses in both diseases. We extensively discuss the use of animal models of both diseases and their relative utilities in modeling human disease. Data presented here from mice exposed to intermittent hypoxia indicate that microglia become more activated following exposure to hypoxia. This also supports the idea that intermittent hypoxia can activate the neuroimmune system in a manner like that seen in AD. Finally, we highlight similarities in the cellular and neuroimmune responses between SDB and AD and propose that these similarities may lead to a pathological synergy between SDB and AD. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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Graphical abstract

23 pages, 780 KiB  
Review
Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders
by Chiara F. Valori, Agostino Possenti, Liliana Brambilla and Daniela Rossi
Cells 2021, 10(8), 2019; https://doi.org/10.3390/cells10082019 - 7 Aug 2021
Cited by 20 | Viewed by 4756
Abstract
Neurodegenerative diseases are a heterogeneous group of disorders whose incidence is likely to duplicate in the next 30 years along with the progressive aging of the western population. Non-cell-specific therapeutics or therapeutics designed to tackle aberrant pathways within neurons failed to slow down [...] Read more.
Neurodegenerative diseases are a heterogeneous group of disorders whose incidence is likely to duplicate in the next 30 years along with the progressive aging of the western population. Non-cell-specific therapeutics or therapeutics designed to tackle aberrant pathways within neurons failed to slow down or halt neurodegeneration. Yet, in the last few years, our knowledge of the importance of glial cells to maintain the central nervous system homeostasis in health conditions has increased exponentially, along with our awareness of their fundamental and multifaced role in pathological conditions. Among glial cells, astrocytes emerge as promising therapeutic targets in various neurodegenerative disorders. In this review, we present the latest evidence showing the astonishing level of specialization that astrocytes display to fulfill the demands of their neuronal partners as well as their plasticity upon injury. Then, we discuss the controversies that fuel the current debate on these cells. We tackle evidence of a potential beneficial effect of cell therapy, achieved by transplanting astrocytes or their precursors. Afterwards, we introduce the different strategies proposed to modulate astrocyte functions in neurodegeneration, ranging from lifestyle changes to environmental cues. Finally, we discuss the challenges and the recent advancements to develop astrocyte-specific delivery systems. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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13 pages, 1252 KiB  
Review
S100A4 in the Physiology and Pathology of the Central and Peripheral Nervous System
by Nadia D’Ambrosi, Martina Milani and Savina Apolloni
Cells 2021, 10(4), 798; https://doi.org/10.3390/cells10040798 - 2 Apr 2021
Cited by 25 | Viewed by 5543
Abstract
S100A4 is a member of the large family of S100 proteins, exerting a broad range of intracellular and extracellular functions that vary upon different cellular contexts. While S100A4 has long been implicated mainly in tumorigenesis and metastatization, mounting evidence shows that S100A4 is [...] Read more.
S100A4 is a member of the large family of S100 proteins, exerting a broad range of intracellular and extracellular functions that vary upon different cellular contexts. While S100A4 has long been implicated mainly in tumorigenesis and metastatization, mounting evidence shows that S100A4 is a key player in promoting pro-inflammatory phenotypes and organ pro-fibrotic pathways in the liver, kidney, lung, heart, tendons, and synovial tissues. Regarding the nervous system, there is still limited information concerning S100A4 presence and function. It was observed that S100A4 exerts physiological roles contributing to neurogenesis, cellular motility and chemotaxis, cell differentiation, and cell-to cell communication. Furthermore, S100A4 is likely to participate to numerous pathological processes of the nervous system by affecting the functions of astrocytes, microglia, infiltrating cells and neurons and thereby modulating inflammation and immune reactions, fibrosis as well as neuronal plasticity and survival. This review summarizes the current state of knowledge concerning the localization, deregulation, and possible functions of S100A4 in the physiology of the central and peripheral nervous system. Furthermore, we highlight S100A4 as a gene involved in the pathogenesis of neurological disorders such as brain tumors, neurodegenerative diseases, and acute injuries. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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17 pages, 1183 KiB  
Review
Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models
by Maria Concetta Geloso and Nadia D’Ambrosi
Cells 2021, 10(3), 686; https://doi.org/10.3390/cells10030686 - 20 Mar 2021
Cited by 37 | Viewed by 6924
Abstract
Microglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or “pruning”) of weaker synapses in both physiologic [...] Read more.
Microglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or “pruning”) of weaker synapses in both physiologic and pathologic processes. Mounting evidence supports their crucial role in early synaptic loss, which is emerging as a hallmark of several neurodegenerative diseases, including multiple sclerosis (MS) and its preclinical models. MS is an inflammatory, immune-mediated pathology of the white matter in which demyelinating lesions may cause secondary neuronal death. Nevertheless, primitive grey matter (GM) damage is emerging as an important contributor to patients’ long-term disability, since it has been associated with early and progressive cognitive decline (CD), which seriously worsens the quality of life of MS patients. Widespread synapse loss even in the absence of demyelination, axon degeneration and neuronal death has been demonstrated in different GM structures, thus raising the possibility that synaptic dysfunction could be an early and possibly independent event in the neurodegenerative process associated with MS. This review provides an overview of microglial-dependent synapse elimination in the neuroinflammatory process that underlies MS and its experimental models. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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25 pages, 4651 KiB  
Review
RNA Localization and Local Translation in Glia in Neurological and Neurodegenerative Diseases: Lessons from Neurons
by Maite Blanco-Urrejola, Adhara Gaminde-Blasco, María Gamarra, Aida de la Cruz, Elena Vecino, Elena Alberdi and Jimena Baleriola
Cells 2021, 10(3), 632; https://doi.org/10.3390/cells10030632 - 12 Mar 2021
Cited by 12 | Viewed by 5359
Abstract
Cell polarity is crucial for almost every cell in our body to establish distinct structural and functional domains. Polarized cells have an asymmetrical morphology and therefore their proteins need to be asymmetrically distributed to support their function. Subcellular protein distribution is typically achieved [...] Read more.
Cell polarity is crucial for almost every cell in our body to establish distinct structural and functional domains. Polarized cells have an asymmetrical morphology and therefore their proteins need to be asymmetrically distributed to support their function. Subcellular protein distribution is typically achieved by localization peptides within the protein sequence. However, protein delivery to distinct cellular compartments can rely, not only on the transport of the protein itself but also on the transport of the mRNA that is then translated at target sites. This phenomenon is known as local protein synthesis. Local protein synthesis relies on the transport of mRNAs to subcellular domains and their translation to proteins at target sites by the also localized translation machinery. Neurons and glia specially depend upon the accurate subcellular distribution of their proteome to fulfil their polarized functions. In this sense, local protein synthesis has revealed itself as a crucial mechanism that regulates proper protein homeostasis in subcellular compartments. Thus, deregulation of mRNA transport and/or of localized translation can lead to neurological and neurodegenerative diseases. Local translation has been more extensively studied in neurons than in glia. In this review article, we will summarize the state-of-the art research on local protein synthesis in neuronal function and dysfunction, and we will discuss the possibility that local translation in glia and deregulation thereof contributes to neurological and neurodegenerative diseases. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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32 pages, 2195 KiB  
Review
Oligodendrocyte Dysfunction in Amyotrophic Lateral Sclerosis: Mechanisms and Therapeutic Perspectives
by Stefano Raffaele, Marta Boccazzi and Marta Fumagalli
Cells 2021, 10(3), 565; https://doi.org/10.3390/cells10030565 - 5 Mar 2021
Cited by 50 | Viewed by 10207
Abstract
Myelin is the lipid-rich structure formed by oligodendrocytes (OLs) that wraps the axons in multilayered sheaths, assuring protection, efficient saltatory signal conduction and metabolic support to neurons. In the last few years, the impact of OL dysfunction and myelin damage has progressively received [...] Read more.
Myelin is the lipid-rich structure formed by oligodendrocytes (OLs) that wraps the axons in multilayered sheaths, assuring protection, efficient saltatory signal conduction and metabolic support to neurons. In the last few years, the impact of OL dysfunction and myelin damage has progressively received more attention and is now considered to be a major contributing factor to neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). Upon OL injury, oligodendrocyte precursor cells (OPCs) of adult nervous tissue sustain the generation of new OLs for myelin reconstitution, but this spontaneous regeneration process fails to successfully counteract myelin damage. Of note, the functions of OPCs exceed the formation and repair of myelin, and also involve the trophic support to axons and the capability to exert an immunomodulatory role, which are particularly relevant in the context of neurodegeneration. In this review, we deeply analyze the impact of dysfunctional OLs in ALS pathogenesis. The possible mechanisms underlying OL degeneration, defective OPC maturation, and impairment in energy supply to motor neurons (MNs) have also been examined to provide insights on future therapeutic interventions. On this basis, we discuss the potential therapeutic utility in ALS of several molecules, based on their remyelinating potential or capability to enhance energy metabolism. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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19 pages, 2742 KiB  
Review
Astrocytes in Alzheimer’s Disease: Pathological Significance and Molecular Pathways
by Pranav Preman, Maria Alfonso-Triguero, Elena Alberdi, Alexei Verkhratsky and Amaia M. Arranz
Cells 2021, 10(3), 540; https://doi.org/10.3390/cells10030540 - 4 Mar 2021
Cited by 80 | Viewed by 12425
Abstract
Astrocytes perform a wide variety of essential functions defining normal operation of the nervous system and are active contributors to the pathogenesis of neurodegenerative disorders such as Alzheimer’s among others. Recent data provide compelling evidence that distinct astrocyte states are associated with specific [...] Read more.
Astrocytes perform a wide variety of essential functions defining normal operation of the nervous system and are active contributors to the pathogenesis of neurodegenerative disorders such as Alzheimer’s among others. Recent data provide compelling evidence that distinct astrocyte states are associated with specific stages of Alzheimer´s disease. The advent of transcriptomics technologies enables rapid progress in the characterisation of such pathological astrocyte states. In this review, we provide an overview of the origin, main functions, molecular and morphological features of astrocytes in physiological as well as pathological conditions related to Alzheimer´s disease. We will also explore the main roles of astrocytes in the pathogenesis of Alzheimer´s disease and summarize main transcriptional changes and altered molecular pathways observed in astrocytes during the course of the disease. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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24 pages, 433 KiB  
Review
Skeletal Muscle in ALS: An Unappreciated Therapeutic Opportunity?
by Silvia Scaricamazza, Illari Salvatori, Alberto Ferri and Cristiana Valle
Cells 2021, 10(3), 525; https://doi.org/10.3390/cells10030525 - 2 Mar 2021
Cited by 36 | Viewed by 5604
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons and by the progressive weakness and paralysis of voluntary muscles. Despite intense research efforts and numerous clinical trials, it is still an incurable disease. [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons and by the progressive weakness and paralysis of voluntary muscles. Despite intense research efforts and numerous clinical trials, it is still an incurable disease. ALS had long been considered a pure motor neuron disease; however, recent studies have shown that motor neuron protection is not sufficient to prevent the course of the disease since the dismantlement of neuromuscular junctions occurs before motor neuron degeneration. Skeletal muscle alterations have been described in the early stages of the disease, and they seem to be mainly involved in the “dying back” phenomenon of motor neurons and metabolic dysfunctions. In recent years, skeletal muscles have been considered crucial not only for the etiology of ALS but also for its treatment. Here, we review clinical and preclinical studies that targeted skeletal muscles and discuss the different approaches, including pharmacological interventions, supplements or diets, genetic modifications, and training programs. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
18 pages, 1653 KiB  
Review
How Degeneration of Cells Surrounding Motoneurons Contributes to Amyotrophic Lateral Sclerosis
by Roxane Crabé, Franck Aimond, Philippe Gosset, Frédérique Scamps and Cédric Raoul
Cells 2020, 9(12), 2550; https://doi.org/10.3390/cells9122550 - 27 Nov 2020
Cited by 20 | Viewed by 6491
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by the progressive degeneration of upper and lower motoneurons. Despite motoneuron death being recognized as the cardinal event of the disease, the loss of glial cells and interneurons in the brain and spinal [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by the progressive degeneration of upper and lower motoneurons. Despite motoneuron death being recognized as the cardinal event of the disease, the loss of glial cells and interneurons in the brain and spinal cord accompanies and even precedes motoneuron elimination. In this review, we provide striking evidence that the degeneration of astrocytes and oligodendrocytes, in addition to inhibitory and modulatory interneurons, disrupt the functionally coherent environment of motoneurons. We discuss the extent to which the degeneration of glial cells and interneurons also contributes to the decline of the motor system. This pathogenic cellular network therefore represents a novel strategic field of therapeutic investigation. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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