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Neurotrophic Factors in Health and Disease

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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 (15 June 2021) | Viewed by 42154

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Dr. Cinzia Severini

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Guest Editor

Institute of Biochemistry and Cell Biology (IBBC),Unit of Translational Biomolecular Medicine “Rita Levi Montalcini", National Research Council of Italy (CNR), Rome, Italy
Interests: neuropeptides and neurodegenerative diseases; pharmacology of neurotrophic factors

Special Issue Information

Dear Colleagues,

Neurotrophic factors, among them neuropeptides and neurotrophins, are secreted proteins regulating survival, development, and physiological function of neurons in both the central and peripheral nervous system. These factors are not only essential for normal neuron activity but can also play a role in neurodegeneration after trauma, ischemia, and neuroinflammation. Deficiencies of neurotrophic factors or deregulation of their cognate receptors is causally associated with the onset and the progression of neurodegenerative diseases, i.e., Alzheimer’s disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD).

The aim of this Special Issue entitled “Neurotrophic factors in health and disease” is to summarize current knowledge of the role of neurotrophic factors in health and disease, focusing on the complex cell biology and pharmacology of these factors at cellular, molecular, and clinical level.

We welcome the submission of original and review articles covering a comprehensive range of biological and pharmacological aspects related to neuropeptides and neurotrophins, and their role in diagnostic and/or therapeutic approach for the management of neurodegenerative diseases.

Dr. Cinzia Severini
Guest Editor

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Keywords

Cellular and molecular aspects of neurotrophic factors
Neurotrophins
Neurological diseases
Neuropeptides
Basic and translational pharmacology

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Published Papers (10 papers)

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Editorial

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3 pages, 196 KiB

Open AccessEditorial

Neurotrophic Factors in Health and Disease

by Cinzia Severini

Cells 2023, 12(1), 47; https://doi.org/10.3390/cells12010047 - 22 Dec 2022

Cited by 5 | Viewed by 1432

Abstract

Neurotrophic factors, including neurotrophins and neuropeptides, are secreted proteins that regulate the survival, development, and physiological functions of neurons in both the central and peripheral nervous systems [...] Full article

(This article belongs to the Special Issue Neurotrophic Factors in Health and Disease)

Research

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23 pages, 7578 KiB

Open AccessArticle

Transcriptional Profiles of Cell Fate Transitions Reveal Early Drivers of Neuronal Apoptosis and Survival

by Giovanna Morello, Ambra Villari, Antonio Gianmaria Spampinato, Valentina La Cognata, Maria Guarnaccia, Giulia Gentile, Maria Teresa Ciotti, Pietro Calissano, Velia D’Agata, Cinzia Severini and Sebastiano Cavallaro

Cells 2021, 10(11), 3238; https://doi.org/10.3390/cells10113238 - 19 Nov 2021

Cited by 3 | Viewed by 3577

Abstract

Neuronal apoptosis and survival are regulated at the transcriptional level. To identify key genes and upstream regulators primarily responsible for these processes, we overlayed the temporal transcriptome of cerebellar granule neurons following induction of apoptosis and their rescue by three different neurotrophic factors. We identified a core set of 175 genes showing opposite expression trends at the intersection of apoptosis and survival. Their functional annotations and expression signatures significantly correlated to neurological, psychiatric and oncological disorders. Transcription regulatory network analysis revealed the action of nine upstream transcription factors, converging pro-apoptosis and pro-survival-inducing signals in a highly interconnected functionally and temporally ordered manner. Five of these transcription factors are potential drug targets. Transcriptome-based computational drug repurposing produced a list of drug candidates that may revert the apoptotic core set signature. Besides elucidating early drivers of neuronal apoptosis and survival, our systems biology-based perspective paves the way to innovative pharmacology focused on upstream targets and regulatory networks. Full article

(This article belongs to the Special Issue Neurotrophic Factors in Health and Disease)

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18 pages, 4276 KiB

Open AccessArticle

Nerve Growth Factor Neutralization Promotes Oligodendrogenesis by Increasing miR-219a-5p Levels

by Rossella Brandi, Marietta Fabiano, Corinna Giorgi, Ivan Arisi, Federico La Regina, Francesca Malerba, Sabrina Turturro, Andrea Ennio Storti, Flavia Ricevuti, Susanna Amadio, Cinzia Volontè, Simona Capsoni, Raffaella Scardigli, Mara D’Onofrio and Antonino Cattaneo

Cells 2021, 10(2), 405; https://doi.org/10.3390/cells10020405 - 16 Feb 2021

Cited by 10 | Viewed by 3111

Abstract

In the brain, the neurotrophin Nerve growth factor (NGF) regulates not only neuronal survival and differentiation, but also glial and microglial functions and neuroinflammation. NGF is known to regulate oligodendrogenesis, reducing myelination in the central nervous system (CNS). In this study, we found that NGF controls oligodendrogenesis by modulating the levels of miR-219a-5p, a well-known positive regulator of oligodendrocyte differentiation. We exploited an NGF-deprivation mouse model, the AD11 mice, in which the postnatal expression of an anti-NGF antibody leads to NGF neutralization and progressive neurodegeneration. Notably, we found that these mice also display increased myelination. A microRNA profiling of AD11 brain samples and qRT-PCR analyses revealed that NGF deprivation leads to an increase of miR-219a-5p levels in hippocampus and cortex and a corresponding down-regulation of its predicted targets. Neurospheres isolated from the hippocampus of AD11 mice give rise to more oligodendrocytes and this process is dependent on miR-219a-5p, as shown by decoy-mediated inhibition of this microRNA. Moreover, treatment of AD11 neurospheres with NGF inhibits miR-219a-5p up-regulation and, consequently, oligodendrocyte differentiation, while anti-NGF treatment of wild type (WT) oligodendrocyte progenitors increases miR-219a-5p expression and the number of mature cells. Overall, this study indicates that NGF inhibits oligodendrogenesis and myelination by down-regulating miR-219a-5p levels, suggesting a novel molecular circuitry that can be exploited for the discovery of new effectors for remyelination in human demyelinating diseases, such as Multiple Sclerosis. Full article

(This article belongs to the Special Issue Neurotrophic Factors in Health and Disease)

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16 pages, 11440 KiB

Open AccessArticle

Social Defeat Stress during Early Adolescence Confers Resilience against a Single Episode of Prolonged Stress in Adult Rats

by Giulia Federica Mancini, Enrico Marchetta, Irene Pignani, Viviana Trezza and Patrizia Campolongo

Cells 2021, 10(2), 360; https://doi.org/10.3390/cells10020360 - 9 Feb 2021

Cited by 16 | Viewed by 3690

Abstract

Early-life adverse experiences (first hit) lead to coping strategies that may confer resilience or vulnerability to later experienced stressful events (second hit) and the subsequent development of stress-related psychopathologies. Here, we investigated whether exposure to two stressors at different stages in life has long-term effects on emotional and cognitive capabilities, and whether the interaction between the two stressors influences stress resilience. Male rats were subjected to social defeat stress (SDS, first hit) in adolescence and to a single episode of prolonged stress (SPS, second hit) in adulthood. Behavioral outcomes, hippocampal expression of brain-derived neurotrophic factor, and plasma corticosterone levels were tested in adulthood. Rats exposed to both stressors exhibited resilience against the development of stress-induced alterations in emotional behaviors and spatial memory, but vulnerability to cued fear memory dysfunction. Rats subjected to both stressors demonstrated resilience against the SDS-induced alterations in hippocampal brain-derived neurotrophic factor expression and plasma corticosterone levels. SPS alone altered locomotion and spatial memory retention; these effects were absent in SDS-exposed rats later exposed to SPS. Our findings reveal that exposure to social stress during early adolescence influences the ability to cope with a second challenge experienced later in life. Full article

(This article belongs to the Special Issue Neurotrophic Factors in Health and Disease)

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16 pages, 3041 KiB

Open AccessArticle

Involvement of Bradykinin Receptor 2 in Nerve Growth Factor Neuroprotective Activity

by Carla Petrella, Maria Teresa Ciotti, Robert Nisticò, Sonia Piccinin, Pietro Calissano, Simona Capsoni, Delio Mercanti, Sebastiano Cavallaro, Roberta Possenti and Cinzia Severini

Cells 2020, 9(12), 2651; https://doi.org/10.3390/cells9122651 - 10 Dec 2020

Cited by 7 | Viewed by 3234

Abstract

Neurotrophin nerve growth factor (NGF) has been demonstrated to upregulate the gene expression of bradykinin receptor 2 (B2R) on sensory neurons, thus facilitating nociceptive signals. The aim of the present study is to investigate the involvement of B2R in the NGF mechanism of action in nonsensory neurons in vitro by using rat mixed cortical primary cultures (CNs) and mouse hippocampal slices, and in vivo in Alzheimer’s disease (AD) transgenic mice (5xFAD) chronically treated with NGF. A significant NGF-mediated upregulation of B2R was demonstrated by microarray, Western blot, and immunofluorescence analysis in CNs, indicating microglial cells as the target of this modulation. The B2R involvement in the NGF mechanism of action was also demonstrated by using a selective B2R antagonist which was able to reverse the neuroprotective effect of NGF in CNs, as revealed by viability assay, and the NGF-induced long-term potentiation (LTP) in hippocampal slices. To confirm in vitro observations, B2R upregulation was observed in 5xFAD mouse brain following chronic intranasal NGF treatment. This study demonstrates for the first time that B2R is a key element in the neuroprotective activity and synaptic plasticity mediated by NGF in brain cells. Full article

(This article belongs to the Special Issue Neurotrophic Factors in Health and Disease)

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20 pages, 7268 KiB

Open AccessArticle

ProNGF/p75NTR Axis Drives Fiber Type Specification by Inducing the Fast-Glycolytic Phenotype in Mouse Skeletal Muscle Cells

by Valentina Pallottini, Mayra Colardo, Claudia Tonini, Noemi Martella, Georgios Strimpakos, Barbara Colella, Paola Tirassa, Sabrina Di Bartolomeo and Marco Segatto

Cells 2020, 9(10), 2232; https://doi.org/10.3390/cells9102232 - 2 Oct 2020

Cited by 8 | Viewed by 4859

Abstract

Despite its undisputable role in the homeostatic regulation of the nervous system, the nerve growth factor (NGF) also governs the relevant cellular processes in other tissues and organs. In this study, we aimed at assessing the expression and the putative involvement of NGF signaling in skeletal muscle physiology. To reach this objective, we employed satellite cell-derived myoblasts as an in vitro culture model. In vivo experiments were performed on Tibialis anterior from wild-type mice and an mdx mouse model of Duchenne muscular dystrophy. Targets of interest were mainly assessed by means of morphological, Western blot and qRT-PCR analysis. The results show that proNGF is involved in myogenic differentiation. Importantly, the proNGF/p75NTR pathway orchestrates a slow-to-fast fiber type transition by counteracting the expression of slow myosin heavy chain and that of oxidative markers. Concurrently, proNGF/p75NTR activation facilitates the induction of fast myosin heavy chain and of fast/glycolytic markers. Furthermore, we also provided evidence that the oxidative metabolism is impaired in mdx mice, and that these alterations are paralleled by a prominent buildup of proNGF and p75NTR. These findings underline that the proNGF/p75NTR pathway may play a crucial role in fiber type determination and suggest its prospective modulation as an innovative therapeutic approach to counteract muscle disorders. Full article

(This article belongs to the Special Issue Neurotrophic Factors in Health and Disease)

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14 pages, 1806 KiB

Open AccessArticle

Impact of BDNF Val66Met Polymorphism on Myocardial Infarction: Exploring the Macrophage Phenotype

by Leonardo Sandrini, Laura Castiglioni, Patrizia Amadio, José Pablo Werba, Sonia Eligini, Susanna Fiorelli, Marta Zarà, Silvia Castiglioni, Stefano Bellosta, Francis S. Lee, Luigi Sironi, Elena Tremoli and Silvia Stella Barbieri

Cells 2020, 9(5), 1084; https://doi.org/10.3390/cells9051084 - 27 Apr 2020

Cited by 17 | Viewed by 3556

Abstract

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin growth factor family, well known for its role in the homeostasis of the cardiovascular system. Recently, the human BDNF Val66Met single nucleotide polymorphism has been associated with the increased propensity for arterial thrombosis related to acute myocardial infarction (AMI). Using cardiac magnetic resonance imaging and immunohistochemistry analyses, we showed that homozygous mice carrying the human BDNF Val66Met polymorphism (BDNF^Met/Met) undergoing left anterior descending (LAD) coronary artery ligation display an adverse cardiac remodeling compared to wild-type (BDNF^Val/Val). Interestingly, we observed a persistent presence of pro-inflammatory M1-like macrophages and a reduced accumulation of reparative-like phenotype macrophages (M2-like) in the infarcted heart of mutant mice. Further qPCR analyses showed that BDNF^Met/Met peritoneal macrophages are more pro-inflammatory and have a higher migratory ability compared to BDNF^Val/Val ones. Finally, macrophages differentiated from circulating monocytes isolated from BDNF^Met/Met patients with coronary heart disease displayed the same pro-inflammatory characteristics of the murine ones. In conclusion, the BDNF Val66Met polymorphism predisposes to adverse cardiac remodeling after myocardial infarction in a mouse model and affects macrophage phenotype in both humans and mice. These results provide a new cellular mechanism by which this human BDNF genetic variant could influence cardiovascular disease. Full article

(This article belongs to the Special Issue Neurotrophic Factors in Health and Disease)

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9 pages, 2065 KiB

Open AccessCommunication

VEGF Treatment Ameliorates Depression-Like Behavior in Adult Offspring after Maternal Immune Activation

by Spyridon Sideromenos, Claudia Lindtner, Alice Zambon, Orsolya Horvath, Angelika Berger and Daniela D. Pollak

Cells 2020, 9(4), 1048; https://doi.org/10.3390/cells9041048 - 22 Apr 2020

Cited by 15 | Viewed by 3216

Abstract

Maternal immune activation (MIA) during pregnancy impacts offspring neurodevelopmental trajectories and induces lifelong consequences, including emotional and cognitive alterations. Using the polyinosinic:polycytidilic acid (PIC) MIA model we have previously demonstrated enhanced depression-like behavior in adult MIA offspring, which was associated with reduced expression of the vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) in the hippocampus. Since VEGF mediates the effects of various antidepressant agents, we here set out to explore whether VEGF administration could rescue the depression-like behavioral deficits in MIA offspring. To test our hypothesis, control and MIA offspring were intracerebroventricularly (i.c.v.) infused with either VEGF or vehicle solution and depression-related behavior was assessed in the sucrose preference test (SPT) and the tail suspension test (TST). As a surrogate of VEGF activity, the phosphorylation of the extracellular signal-regulated kinase (ERK) in hippocampus was quantified. We found that VEGF treatment reduced depression-related behavioral despair in the TST in MIA offspring but had no effect on anhedonia-like behavior in the SPT. While VEGF administration induced the phosphorylation of ERK in the hippocampus of control offspring, this effect was blunted in the MIA offspring. We conclude that VEGF administration, at the dosage tested, beneficially affects some aspects of the depression-like phenotype in the adult MIA offspring, inviting further studies using different dosage regimes to further explore the therapeutic potential of VEGF treatment in MIA-related changes in brain function and behavior. Full article

(This article belongs to the Special Issue Neurotrophic Factors in Health and Disease)

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21 pages, 9006 KiB

Open AccessArticle

Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation

by Paola Saveri, Maria De Luca, Veronica Nisi, Chiara Pisciotta, Roberta Romano, Giuseppe Piscosquito, Mary M. Reilly, James M. Polke, Tiziana Cavallaro, Gian Maria Fabrizi, Paola Fossa, Elena Cichero, Raffaella Lombardi, Giuseppe Lauria, Stefania Magri, Franco Taroni, Davide Pareyson and Cecilia Bucci

Cells 2020, 9(4), 1028; https://doi.org/10.3390/cells9041028 - 21 Apr 2020

Cited by 21 | Viewed by 4619

Abstract

The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the RAB7A gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic RAB7A variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking difficulties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs. Electrophysiology demonstrated an axonal sensorimotor neuropathy. Nerve biopsy showed a chronic axonal neuropathy with moderate loss of all caliber myelinated fibers. Next-generation sequencing (NGS) technology revealed in the proband and in her similarly affected father the novel c.377A>G (p.K126R) heterozygous variant predicted to be deleterious. The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. However, it also shows differences, particularly in the epidermal growth factor receptor degradation process. Altogether, our findings indicate that this RAB7A variant is pathogenic and widens the phenotypic spectrum of CMT2B to include predominantly motor CMT2. Alteration of the receptor degradation process might explain the different clinical presentations in this family. Full article

(This article belongs to the Special Issue Neurotrophic Factors in Health and Disease)

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16 pages, 1265 KiB

Open AccessCommentary

Putting Cells in Motion: Advantages of Endogenous Boosting of BDNF Production

by Elvira Brattico, Leonardo Bonetti, Gabriella Ferretti, Peter Vuust and Carmela Matrone

Cells 2021, 10(1), 183; https://doi.org/10.3390/cells10010183 - 18 Jan 2021

Cited by 11 | Viewed by 9581

Abstract

Motor exercise, such as sport or musical activities, helps with a plethora of diseases by modulating brain functions in neocortical and subcortical regions, resulting in behavioural changes related to mood regulation, well-being, memory, and even cognitive preservation in aging and neurodegenerative diseases. Although evidence is accumulating on the systemic neural mechanisms mediating these brain effects, the specific mechanisms by which exercise acts upon the cellular level are still under investigation. This is particularly the case for music training, a much less studied instance of motor exercise than sport. With regards to sport, consistent neurobiological research has focused on the brain-derived neurotrophic factor (BDNF), an essential player in the central nervous system. BDNF stimulates the growth and differentiation of neurons and synapses. It thrives in the hippocampus, the cortex, and the basal forebrain, which are the areas vital for memory, learning, and higher cognitive functions. Animal models and neurocognitive experiments on human athletes converge in demonstrating that physical exercise reliably boosts BDNF levels. In this review, we highlight comparable early findings obtained with animal models and elderly humans exposed to musical stimulation, showing how perceptual exposure to music might affect BDNF release, similar to what has been observed for sport. We subsequently propose a novel hypothesis that relates the neuroplastic changes in the human brains after musical training to genetically- and exercise-driven BDNF levels. Full article

(This article belongs to the Special Issue Neurotrophic Factors in Health and Disease)

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