Special Issue "Key Signalling Molecules in Aging and Neurodegeneration"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling and Regulated Cell Death".

Deadline for manuscript submissions: 15 June 2021.

Special Issue Editors

Prof. Paola Pizzo
Website
Guest Editor
Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
Interests: Ca2+ homeostasis; mitochondria; endoplasmic reticulum; oraganelle contact sites; MAM; bioenergetics; Alzheimer's disease; presenilin; neurodegeneration
Dr. Riccardo Filadi
Website
Assistant Guest Editor
CNR, Neuroscience Institute; Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
Interests: Ca2+ homeostasis; Alzheimer's disease; presenilin; neurodegeneration; mitochondria; endoplasmic reticulum; organelle contact sites; MAM; bioenergetics; metabolism

Special Issue Information

Dear Colleagues,

The human lifespan has drastically increased in the past decades and the percentage of the aged population is constantly rising, posing major health and economic challenges. Aging invariably increases the risk of several diseases, such as those linked to neurodegeneration, cancer, stroke and diabetes. In this Special Issue, the focus will be on neurodegenerative disorders of the elderly, particularly Parkinson and Alzheimer diseases. Both conditions are characterized by the progressive degeneration of specific neuronal circuits, through largely unknown pathogenic mechanisms, and are devoid of valid therapeutic approaches. Therefore, the need to find novel targets and early biomarkers to develop appropriate pharmacological strategies appears urgent. In this scenario, precise knowledge of the specific cellular and molecular processes behind aging and neurodegeneration is a priority for the scientific community.
The aim of this Special Issue is to provide an overview of the main signalling pathways and molecules involved in the process of aging, highlighting their intimate connection with the onset of neurodegenerative disorders.

Prof. Paola Pizzo
Dr. Riccardo Filadi
Guest Editors

Manuscript Submission Information

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Keywords

  • aging
  • neurodegeneration
  • calcium
  • oxidative stress
  • cAMP
  • mitochondria
  • proteostasis
  • autophagy
  • immunity
  • inflammation
  • senescence
  • ER stress
  • UPR
  • Alzheimer
  • metabolism

Published Papers (23 papers)

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Open AccessArticle
Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models
Cells 2020, 9(12), 2552; https://doi.org/10.3390/cells9122552 - 28 Nov 2020
Abstract
Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria–ER contact sites (MERCS) are altered in Alzheimer’s disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as [...] Read more.
Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria–ER contact sites (MERCS) are altered in Alzheimer’s disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aβ as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aβ increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aβ. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER–mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aβ can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessFeature PaperArticle
Overexpression of α-Synuclein by Oligodendrocytes in Transgenic Mice Does Not Recapitulate the Fibrillar Aggregation Seen in Multiple System Atrophy
Cells 2020, 9(11), 2371; https://doi.org/10.3390/cells9112371 - 29 Oct 2020
Abstract
The synucleinopathy underlying multiple system atrophy (MSA) is characterized by the presence of abundant amyloid inclusions containing fibrillar α-synuclein (α-syn) aggregates in the brains of the patients and is associated with an extensive neurodegeneration. In contrast to Parkinson’s disease (PD) where the pathological [...] Read more.
The synucleinopathy underlying multiple system atrophy (MSA) is characterized by the presence of abundant amyloid inclusions containing fibrillar α-synuclein (α-syn) aggregates in the brains of the patients and is associated with an extensive neurodegeneration. In contrast to Parkinson’s disease (PD) where the pathological α-syn aggregates are almost exclusively neuronal, the α-syn inclusions in MSA are principally observed in oligodendrocytes (OLs) where they form glial cytoplasmic inclusions (GCIs). This is intriguing because differentiated OLs express low levels of α-syn, yet pathogenic amyloid α-syn seeds require significant amounts of α-syn monomers to feed their fibrillar growth and to eventually cause the buildup of cytopathological inclusions. One of the transgenic mouse models of this disease is based on the targeted overexpression of human α-syn in OLs using the PLP promoter. In these mice, the histopathological images showing a rapid emergence of S129-phosphorylated α-syn inside OLs are considered as equivalent to GCIs. Instead, we report here that they correspond to the accumulation of phosphorylated α-syn monomers/oligomers and not to the appearance of the distinctive fibrillar α-syn aggregates that are present in the brains of MSA or PD patients. In spite of a propensity to co-sediment with myelin sheath contaminants, the phosphorylated forms found in the brains of the transgenic animals are soluble (>80%). In clear contrast, the phosphorylated species present in the brains of MSA and PD patients are insoluble fibrils (>95%). Using primary cultures of OLs from PLP-αSyn mice we observed a variable association of S129-phosphorylated α-syn with the cytoplasmic compartment, the nucleus and with membrane domains suggesting that OLs functionally accommodate the phospho-α-syn deriving from experimental overexpression. Yet and while not taking place spontaneously, fibrillization can be seeded in these primary cultures by challenging the OLs with α-syn preformed fibrils (PFFs). This indicates that a targeted overexpression of α-syn does not model GCIs in mice but that it can provide a basis for seeding aggregation using PFFs. This approach could help establishing a link between α-syn aggregation and the development of a clinical phenotype in these transgenic animals. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Molecular Genetics and Functional Analysis Implicate CDKN2BAS1-CDKN2B Involvement in POAG Pathogenesis
Cells 2020, 9(9), 1934; https://doi.org/10.3390/cells9091934 - 21 Aug 2020
Abstract
The genes in the 9p21 locus (CDKN2B-AS1 & CDKN2B) are widely associated with Primary open-angle glaucoma (POAG). However, the functional importance of this locus in POAG pathogenesis is still unexplored. This study investigated the role of CDKN2BAS1-CDKN2B axis in POAG. We [...] Read more.
The genes in the 9p21 locus (CDKN2B-AS1 & CDKN2B) are widely associated with Primary open-angle glaucoma (POAG). However, the functional importance of this locus in POAG pathogenesis is still unexplored. This study investigated the role of CDKN2BAS1-CDKN2B axis in POAG. We observed significant association of CDKN2B-AS1 SNP rs4977756 with POAG and its endophenotypic traits (vertical cup-disc ratio (p = 0.033) and central corneal thickness (p = 0.008)) by screening African American POAG cases (n = 1567) and controls (n = 1600). A luciferase reporter assay in Human embryonic kidney 293T (HEK293T) cells revealed that the region surrounding rs4977756 likely serves as a transcriptional repressor. siRNA-mediated knockdown of CDKN2B-AS1 in HEK293T cells and trabecular meshwork (TM) cells resulted in significantly increased expression of CDKN2B, which was also observed in human POAG ocular tissues. Pathway focused qRT-PCR gene expression analysis showed increased cellular senescence, TGFβ signaling and ECM deposition in TM cells after CDKN2B-AS1 suppression. In conclusion, we report that CDKN2B-AS1 may act as a regulator, and it could function by modulating the expression of CDKN2B. In addition, increase in CDKN2B levels due to CDKN2B-AS1 suppression may result in the senescence of trabecular meshwork cells leading to POAG pathogenesis. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Fyn Tyrosine Kinase Elicits Amyloid Precursor Protein Tyr682 Phosphorylation in Neurons from Alzheimer’s Disease Patients
Cells 2020, 9(8), 1807; https://doi.org/10.3390/cells9081807 - 30 Jul 2020
Cited by 1
Abstract
Alzheimer’s disease (AD) is an incurable neurodegenerative disorder with a few early detection strategies. We previously proposed the amyloid precursor protein (APP) tyrosine 682 (Tyr682) residue as a valuable target for the development of new innovative pharmacologic or diagnostic interventions in AD. Indeed, [...] Read more.
Alzheimer’s disease (AD) is an incurable neurodegenerative disorder with a few early detection strategies. We previously proposed the amyloid precursor protein (APP) tyrosine 682 (Tyr682) residue as a valuable target for the development of new innovative pharmacologic or diagnostic interventions in AD. Indeed, when APP is phosphorylated at Tyr682, it is forced into acidic neuronal compartments where it is processed to generate neurotoxic amyloid β peptides. Of interest, Fyn tyrosine kinase (TK) interaction with APP Tyr682 residue increases in AD neurons. Here we proved that when Fyn TK was overexpressed it elicited APP Tyr682 phosphorylation in neurons from healthy donors and promoted the amyloidogenic APP processing with Aβ peptides accumulation and neuronal death. Phosphorylation of APP at Tyr (pAPP-Tyr) increased in neurons of AD patients and AD neurons that exhibited high pAPP-Tyr also had higher Fyn TK activity. Fyn TK inhibition abolished the pAPP-Tyr and reduced Aβ42 secretion in AD neurons. In addition, the multidomain adaptor protein Fe65 controlled the Fyn-mediated pAPP-Tyr, warranting the possibility of targeting the Fe65-APP-Fyn pathway to develop innovative strategies in AD. Altogether, these results strongly emphasize the relevance of focusing on pAPP Tyr682 either for diagnostic purposes, as an early biomarker of the disease, or for pharmacological targeting, using Fyn TKI. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
The Pluripotency Factor Nanog Protects against Neuronal Amyloid β-Induced Toxicity and Oxidative Stress through Insulin Sensitivity Restoration
Cells 2020, 9(6), 1339; https://doi.org/10.3390/cells9061339 - 27 May 2020
Abstract
Amyloid β (Aβ) is a peptide fragment of the amyloid precursor protein that triggers the progression of Alzheimer’s Disease (AD). It is believed that Aβ contributes to neurodegeneration in several ways, including mitochondria dysfunction, oxidative stress and brain insulin resistance. Therefore, protecting neurons [...] Read more.
Amyloid β (Aβ) is a peptide fragment of the amyloid precursor protein that triggers the progression of Alzheimer’s Disease (AD). It is believed that Aβ contributes to neurodegeneration in several ways, including mitochondria dysfunction, oxidative stress and brain insulin resistance. Therefore, protecting neurons from Aβ-induced neurotoxicity is an effective strategy for attenuating AD pathogenesis. Recently, applications of stem cell-based therapies have demonstrated the ability to reduce the progression and outcome of neurodegenerative diseases. Particularly, Nanog is recognized as a stem cell-related pluripotency factor that enhances self-renewing capacities and helps reduce the senescent phenotypes of aged neuronal cells. However, whether the upregulation of Nanog can be an effective approach to alleviate Aβ-induced neurotoxicity and senescence is not yet understood. In the present study, we transiently overexpressed Nanog—both in vitro and in vivo—and investigated the protective effects and underlying mechanisms against Aβ. We found that overexpression of Nanog is responsible for attenuating Aβ-triggered neuronal insulin resistance, which restores cell survival through reducing intracellular mitochondrial superoxide accumulation and cellular senescence. In addition, upregulation of Nanog expression appears to increase secretion of neurotrophic factors through activation of the Nrf2 antioxidant defense pathway. Furthermore, improvement of memory and learning were also observed in rat model of Aβ neurotoxicity mediated by upregulation of Nanog in the brain. Taken together, our study suggests a potential role for Nanog in attenuating the neurotoxic effects of Aβ, which in turn, suggests that strategies to enhance Nanog expression may be used as a novel intervention for reducing Aβ neurotoxicity in the AD brain. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessFeature PaperArticle
Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices
Cells 2020, 9(3), 664; https://doi.org/10.3390/cells9030664 - 09 Mar 2020
Cited by 3
Abstract
Calcium homeostasis modulator 1 (CALHM1) is a calcium channel involved in the regulation of cytosolic Ca2+ levels. From a physiological point of view, the open state of CALHM1 depends not only on voltage but also on the extracellular concentration of calcium ([Ca [...] Read more.
Calcium homeostasis modulator 1 (CALHM1) is a calcium channel involved in the regulation of cytosolic Ca2+ levels. From a physiological point of view, the open state of CALHM1 depends not only on voltage but also on the extracellular concentration of calcium ([Ca2+]) ions. At low [Ca2+]e or depolarization, the channel is opened, allowing Ca2+ influx; however, high extracellular [Ca2+]e or hyperpolarization promote its resting state. The unique Ca2+ permeation of CALHM1 relates to the molecular events that take place in brain ischemia, such as depolarization and extracellular changes in [Ca2+]e, particularly during the reperfusion phase after the ischemic insult. In this study, we attempted to understand its role in an in vitro model of ischemia, namely oxygen and glucose deprivation, followed by reoxygenation (OGD/Reox). To this end, hippocampal slices from wild-type Calhm1+/+, Calhm1+/−, and Calhm1−/− mice were subjected to OGD/Reox. Our results point out to a neuroprotective effect when CALHM1 is partially or totally absent. Pharmacological manipulation of CALHM1 with CGP37157 reduced cell death in Calhm1+/+ slices but not in that of Calhm1−/− mice after exposure to the OGD/Reox protocol. This ionic protection was also verified by measuring reactive oxygen species production upon OGD/Reox in Calhm1+/+ and Calhm1−/− mice, resulting in a downregulation of ROS production in Calhm1−/− hippocampal slices and increased expression of HIF-1α. Taken together, we can conclude that genetic or pharmacological inhibition of CALHM1 results in a neuroprotective effect against ischemia, due to an attenuation of the neuronal calcium overload and downregulation of oxygen reactive species production. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism
Cells 2020, 9(2), 325; https://doi.org/10.3390/cells9020325 - 30 Jan 2020
Cited by 2
Abstract
Polyglutamine (polyQ) expansions in the androgen receptor (AR) gene cause spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease characterized by lower motor neuron (MN) loss and skeletal muscle atrophy, with an unknown mechanism. We generated new mouse models of SBMA for constitutive [...] Read more.
Polyglutamine (polyQ) expansions in the androgen receptor (AR) gene cause spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease characterized by lower motor neuron (MN) loss and skeletal muscle atrophy, with an unknown mechanism. We generated new mouse models of SBMA for constitutive and inducible expression of mutant AR and performed biochemical, histological and functional analyses of phenotype. We show that polyQ-expanded AR causes motor dysfunction, premature death, IIb-to-IIa/IIx fiber-type change, glycolytic-to-oxidative fiber-type switching, upregulation of atrogenes and autophagy genes and mitochondrial dysfunction in skeletal muscle, together with signs of muscle denervation at late stage of disease. PolyQ expansions in the AR resulted in nuclear enrichment. Within the nucleus, mutant AR formed 2% sodium dodecyl sulfate (SDS)-resistant aggregates and inclusion bodies in myofibers, but not spinal cord and brainstem, in a process exacerbated by age and sex. Finally, we found that two-week induction of expression of polyQ-expanded AR in adult mice was sufficient to cause premature death, body weight loss and muscle atrophy, but not aggregation, metabolic alterations, motor coordination and fiber-type switch, indicating that expression of the disease protein in the adulthood is sufficient to recapitulate several, but not all SBMA manifestations in mice. These results imply that chronic expression of polyQ-expanded AR, i.e. during development and prepuberty, is key to induce the full SBMA muscle pathology observed in patients. Our data support a model whereby chronic expression of polyQ-expanded AR triggers muscle atrophy through toxic (neomorphic) gain of function mechanisms distinct from normal (hypermorphic) gain of function mechanisms. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Dampened Slow Oscillation Connectivity Anticipates Amyloid Deposition in the PS2APP Mouse Model of Alzheimer’s Disease
Cells 2020, 9(1), 54; https://doi.org/10.3390/cells9010054 - 24 Dec 2019
Cited by 3
Abstract
To fight Alzheimer’s disease (AD), we should know when, where, and how brain network dysfunctions initiate. In AD mouse models, relevant information can be derived from brain electrical activity. With a multi-site linear probe, we recorded local field potentials simultaneously at the posterior-parietal [...] Read more.
To fight Alzheimer’s disease (AD), we should know when, where, and how brain network dysfunctions initiate. In AD mouse models, relevant information can be derived from brain electrical activity. With a multi-site linear probe, we recorded local field potentials simultaneously at the posterior-parietal cortex and hippocampus of wild-type and double transgenic AD mice, under anesthesia. We focused on PS2APP (B6.152H) mice carrying both presenilin-2 (PS2) and amyloid precursor protein (APP) mutations, at three and six months of age, before and after plaque deposition respectively. To highlight defects linked to either the PS2 or APP mutation, we included in the analysis age-matched PS2.30H and APP-Swedish mice, carrying each of the mutations individually. Our study also included PSEN2−/− mice. At three months, only predeposition B6.152H mice show a reduction in the functional connectivity of slow oscillations (SO) and in the power ratio between SO and delta waves. At six months, plaque-seeding B6.152H mice undergo a worsening of the low/high frequency power imbalance and show a massive loss of cortico-hippocampal phase-amplitude coupling (PAC) between SO and higher frequencies, a feature shared with amyloid-free PS2.30H mice. We conclude that the PS2 mutation is sufficient to impair SO PAC and accelerate network dysfunctions in amyloid-accumulating mice. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessCommunication
Involvement of the Chemokine Prokineticin-2 (PROK2) in Alzheimer’s Disease: From Animal Models to the Human Pathology
Cells 2019, 8(11), 1430; https://doi.org/10.3390/cells8111430 - 13 Nov 2019
Cited by 2
Abstract
Among mediators of inflammation, chemokines play a pivotal role in the neuroinflammatory process related to Alzheimer’s disease (AD). The chemokine Bv8/prokineticin 2 (PROK2) is a critical player in inflammatory and neuroinflammatory diseases and has been demonstrated to be involved in Aβ toxicity. The [...] Read more.
Among mediators of inflammation, chemokines play a pivotal role in the neuroinflammatory process related to Alzheimer’s disease (AD). The chemokine Bv8/prokineticin 2 (PROK2) is a critical player in inflammatory and neuroinflammatory diseases and has been demonstrated to be involved in Aβ toxicity. The aim of the present study was to extend the research to rats chronically intracerebroventricularly (i.c.v.) injected with Aβ, to an AD transgenic mouse model, and subsequently to AD patients, mainly with the aim of detecting a potential biomarker. Real-time PCR and immunofluorescence analysis were used to evaluate Prokineticin-2 (PROK2) mRNA and the corresponding protein levels in both animal and human AD brain extracts, and the ELISA test was used to measure the amount of PROK2 in the serum of AD patients. We demonstrated a significant upregulation of PROK2 levels in brain tissues of Aβ1–42 i.c.v. injected rats, transgenic AD mice (Tg2576), and in the hippocampus of AD patients. Additionally, through a pilot study, an approximate twofold increase of PROK2 levels has been proved in the serum of AD patients, compared to the control subjects, identifying a potential blood-based biomarker of the disease. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Stromal Cell-Derived Factor 1 Protects Brain Vascular Endothelial Cells from Radiation-Induced Brain Damage
Cells 2019, 8(10), 1230; https://doi.org/10.3390/cells8101230 - 10 Oct 2019
Cited by 3
Abstract
Stromal cell-derived factor 1 (SDF-1) and its main receptor, CXC chemokine receptor 4 (CXCR4), play a critical role in endothelial cell function regulation during cardiogenesis, angiogenesis, and reendothelialization after injury. The expression of CXCR4 and SDF-1 in brain endothelial cells decreases due to [...] Read more.
Stromal cell-derived factor 1 (SDF-1) and its main receptor, CXC chemokine receptor 4 (CXCR4), play a critical role in endothelial cell function regulation during cardiogenesis, angiogenesis, and reendothelialization after injury. The expression of CXCR4 and SDF-1 in brain endothelial cells decreases due to ionizing radiation treatment and aging. SDF-1 protein treatment in the senescent and radiation-damaged cells reduced several senescence phenotypes, such as decreased cell proliferation, upregulated p53 and p21 expression, and increased senescence-associated beta-galactosidase (SA-β-gal) activity, through CXCR4-dependent signaling. By inhibiting extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription protein 3 (STAT3), we confirmed that activation of both is important in recovery by SDF-1-related mechanisms. A CXCR4 agonist, ATI2341, protected brain endothelial cells from radiation-induced damage. In irradiation-damaged tissue, ATI2341 treatment inhibited cell death in the villi of the small intestine and decreased SA-β-gal activity in arterial tissue. An ischemic injury experiment revealed no decrease in blood flow by irradiation in ATI2341-administrated mice. ATI2341 treatment specifically affected CXCR4 action in mouse brain vessels and partially restored normal cognitive ability in irradiated mice. These results demonstrate that SDF-1 and ATI2341 may offer potential therapeutic approaches to recover tissues damaged during chemotherapy or radiotherapy, particularly by protecting vascular endothelial cells. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessCommunication
An Agonist of the CXCR4 Receptor Strongly Promotes Regeneration of Degenerated Motor Axon Terminals
Cells 2019, 8(10), 1183; https://doi.org/10.3390/cells8101183 - 30 Sep 2019
Cited by 5
Abstract
The activation of the G-protein coupled receptor CXCR4 by its ligand CXCL12α is involved in a large variety of physiological and pathological processes, including the growth of B cells precursors and of motor axons, autoimmune diseases, stem cell migration, inflammation, and several neurodegenerative [...] Read more.
The activation of the G-protein coupled receptor CXCR4 by its ligand CXCL12α is involved in a large variety of physiological and pathological processes, including the growth of B cells precursors and of motor axons, autoimmune diseases, stem cell migration, inflammation, and several neurodegenerative conditions. Recently, we demonstrated that CXCL12α potently stimulates the functional recovery of damaged neuromuscular junctions via interaction with CXCR4. This result prompted us to test the neuroregeneration activity of small molecules acting as CXCR4 agonists, endowed with better pharmacokinetics with respect to the natural ligand. We focused on NUCC-390, recently shown to activate CXCR4 in a cellular system. We designed a novel and convenient chemical synthesis of NUCC-390, which is reported here. NUCC-390 was tested for its capability to induce the regeneration of motor axon terminals completely degenerated by the presynaptic neurotoxin α-Latrotoxin. NUCC-390 was found to strongly promote the functional recovery of the neuromuscular junction, as assayed by electrophysiology and imaging. This action is CXCR4 dependent, as it is completely prevented by AMD3100, a well-characterized CXCR4 antagonist. These data make NUCC-390 a strong candidate to be tested in human therapy to promote nerve recovery of function after different forms of neurodegeneration. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Deregulated miR-29b-3p Correlates with Tissue-Specific Activation of Intrinsic Apoptosis in An Animal Model of Amyotrophic Lateral Sclerosis
Cells 2019, 8(9), 1077; https://doi.org/10.3390/cells8091077 - 12 Sep 2019
Cited by 3
Abstract
Amyotrophic lateral sclerosis (ALS) is one of the most common incurable motor neuron disorders in adults. The majority of all ALS cases occur sporadically (sALS). Symptoms of ALS are caused by a progressive degeneration of motor neurons located in the motor cortex and [...] Read more.
Amyotrophic lateral sclerosis (ALS) is one of the most common incurable motor neuron disorders in adults. The majority of all ALS cases occur sporadically (sALS). Symptoms of ALS are caused by a progressive degeneration of motor neurons located in the motor cortex and spinal cord. The question arises why motor neurons selectively degenerate in ALS, while other cells and systems appear to be spared the disease. Members of the intrinsic apoptotic pathway are frequent targets of altered microRNA expression. Therefore, microRNAs and their effects on cell survival are subject of controversial debates. In this study, we investigated the expression of numerous members of the intrinsic apoptotic cascade by qPCR, western blot, and immunostaining in two different regions of the CNS of wobbler mice. Further we addressed the expression of miR-29b-3p targeting BMF, Bax, and, Bak, members of the apoptotic pathway. We show a tissue-specific differential expression of BMF, Bax, and cleaved-Caspase 3 in wobbler mice. An opposing regulation of miR-29b-3p expression in the cerebellum and cervical spinal cord of wobbler mice suggests different mechanisms regulating the intrinsic apoptotic pathway. Based on our findings, it could be speculated that miR-29b-3p might regulate antiapoptotic survival mechanisms in CNS areas that are not affected by neurodegeneration in the wobbler mouse ALS model. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Free-Water Imaging in White and Gray Matter in Parkinson’s Disease
Cells 2019, 8(8), 839; https://doi.org/10.3390/cells8080839 - 05 Aug 2019
Cited by 8
Abstract
This study aimed to discriminate between neuroinflammation and neuronal degeneration in the white matter (WM) and gray matter (GM) of patients with Parkinson’s disease (PD) using free-water (FW) imaging. Analysis using tract-based spatial statistics (TBSS) of 20 patients with PD and 20 healthy [...] Read more.
This study aimed to discriminate between neuroinflammation and neuronal degeneration in the white matter (WM) and gray matter (GM) of patients with Parkinson’s disease (PD) using free-water (FW) imaging. Analysis using tract-based spatial statistics (TBSS) of 20 patients with PD and 20 healthy individuals revealed changes in FW imaging indices (i.e., reduced FW-corrected fractional anisotropy (FAT), increased FW-corrected mean, axial, and radial diffusivities (MDT, ADT, and RDT, respectively) and fractional volume of FW (FW) in somewhat more specific WM areas compared with the changes of DTI indices. The region-of-interest (ROI) analysis further supported these findings, whereby those with PD showed significantly lower FAT and higher MDT, ADT, and RDT (indices of neuronal degeneration) in anterior WM areas as well as higher FW (index of neuroinflammation) in posterior WM areas compared with the controls. Results of GM-based spatial statistics (GBSS) analysis revealed that patients with PD had significantly higher MDT, ADT, and FW than the controls, whereas ROI analysis showed significantly increased MDT and FW and a trend toward increased ADT in GM areas, corresponding to Braak stage IV. These findings support the hypothesis that neuroinflammation precedes neuronal degeneration in PD, whereas WM microstructural alterations precede changes in GM. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Isomerization of Asp7 in Beta-Amyloid Enhances Inhibition of the α7 Nicotinic Receptor and Promotes Neurotoxicity
Cells 2019, 8(8), 771; https://doi.org/10.3390/cells8080771 - 25 Jul 2019
Cited by 8
Abstract
Cholinergic dysfunction in Alzheimer’s disease (AD) can be mediated by the neuronal α7 nicotinic acetylcholine receptor (α7nAChR). Beta-amyloid peptide (Aβ) binds to the α7nAChR, disrupting the receptor’s function and causing neurotoxicity. In vivo not only Aβ but also its modified forms can drive [...] Read more.
Cholinergic dysfunction in Alzheimer’s disease (AD) can be mediated by the neuronal α7 nicotinic acetylcholine receptor (α7nAChR). Beta-amyloid peptide (Aβ) binds to the α7nAChR, disrupting the receptor’s function and causing neurotoxicity. In vivo not only Aβ but also its modified forms can drive AD pathogenesis. One of these forms, iso-Aβ (containing an isomerized Asp7 residue), shows an increased neurotoxicity in vitro and stimulates amyloidogenesis in vivo. We suggested that such effects of iso-Aβ are α7nAChR-dependent. Here, using calcium imaging and electrophysiology, we found that iso-Aβ is a more potent inhibitor of the α7nAChR-mediated calcium current than unmodified Aβ. However, Asp7 isomerization eliminated the ability of Aβ to decrease the α7nAChR levels. These data indicate differences in the interaction of the peptides with the α7nAChR, which we demonstrated using computer modeling. Neither Aβ nor iso-Aβ competed with 125I-α-bungarotoxin for binding to the orthosteric site of the receptor, suggesting the allosteric binging mode of the peptides. Further we found that increased neurotoxicity of iso-Aβ was mediated by the α7nAChR. Thus, the isomerization of Asp7 enhances the inhibitory effect of Aβ on the functional activity of the α7nAChR, which may be an important factor in the disruption of the cholinergic system in AD. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles
Cells 2019, 8(6), 597; https://doi.org/10.3390/cells8060597 - 15 Jun 2019
Cited by 18
Abstract
The maintenance of muscle mass and its ability to function relies on a bioenergetic efficient mitochondrial network. This network is highly impacted by fusion and fission events. We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, [...] Read more.
The maintenance of muscle mass and its ability to function relies on a bioenergetic efficient mitochondrial network. This network is highly impacted by fusion and fission events. We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, systemic inflammatory response, precocious epithelial senescence, and premature death that are caused by muscle-dependent secretion of FGF21. However, both fusion and fission machinery are suppressed in aging sarcopenia, cancer cachexia, and chemotherapy-induced muscle wasting. We generated inducible muscle-specific Opa1 and Drp1 double-knockout mice to address the physiological relevance of the concomitant impairment of fusion and fission machinery in skeletal muscle. Here we show that acute ablation of Opa1 and Drp1 in adult muscle causes the accumulation of abnormal and dysfunctional mitochondria, as well as the inhibition of autophagy and mitophagy pathways. This ultimately results in ER stress, muscle loss, and the reduction of force generation. However, the simultaneous inhibition of the fission protein Drp1 when Opa1 is absent alleviates FGF21 induction, oxidative stress, denervation, and inflammation rescuing the lethal phenotype of Opa1 knockout mice, despite the presence of any muscle weakness. Thus, the simultaneous inhibition of fusion and fission processes mitigates the detrimental effects of unbalanced mitochondrial fusion and prevents the secretion of pro-senescence factors. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
pHluorin-BACE1-mCherry Acts as a Reporter for the Intracellular Distribution of Active BACE1 In Vitro and In Vivo
Cells 2019, 8(5), 474; https://doi.org/10.3390/cells8050474 - 17 May 2019
Cited by 2
Abstract
β-site APP-cleaving enzyme 1 (BACE1) initiates amyloid precursor protein (APP) cleavage and β-amyloid (Aβ) production, a critical step in the pathogenesis of Alzheimer’s disease (AD). It is thus of considerable interest to investigate how BACE1 activity is regulated. BACE1 has its maximal activity [...] Read more.
β-site APP-cleaving enzyme 1 (BACE1) initiates amyloid precursor protein (APP) cleavage and β-amyloid (Aβ) production, a critical step in the pathogenesis of Alzheimer’s disease (AD). It is thus of considerable interest to investigate how BACE1 activity is regulated. BACE1 has its maximal activity at acidic pH and GFP variant—pHluorin—displays pH dependence. In light of these observations, we generated three tandem fluorescence-tagged BACE1 fusion proteins, named pHluorin-BACE1-mCherry, BACE1-mCherry-pHluorin and BACE1-mCherry-EGFP. Comparing the fluorescence characteristics of these proteins in response to intracellular pH changes induced by chloroquine or bafilomycin A1, we found that pHluorin-BACE1-mCherry is a better pH sensor for BACE1 because its fluorescence intensity responds to pH changes more dramatically and more quickly. Additionally, we found that (pro)renin receptor (PRR), a subunit of the v-ATPase complex, which is critical for maintaining vesicular pH, regulates pHluorin’s fluorescence and BACE1 activity in pHluorin-BACE1-mCherry expressing cells. Finally, we found that the expression of Swedish mutant APP (APPswe) suppresses pHluorin fluorescence in pHluorin-BACE1-mCherry expressing cells in culture and in vivo, implicating APPswe not only as a substrate but also as an activator of BACE1. Taken together, these results suggest that the pHluorin-BACE1-mCherry fusion protein may serve as a useful tool for visualizing active/inactive BACE1 in culture and in vivo. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development
Cells 2019, 8(5), 425; https://doi.org/10.3390/cells8050425 - 08 May 2019
Cited by 7
Abstract
As genome-wide association studies (GWAS) have grown in size, the number of genetic variants that have been associated per disease has correspondingly increased. Despite this increase in the number of single-nucleotide polymorphisms (SNPs) identified per disease, their biological interpretation has in many cases [...] Read more.
As genome-wide association studies (GWAS) have grown in size, the number of genetic variants that have been associated per disease has correspondingly increased. Despite this increase in the number of single-nucleotide polymorphisms (SNPs) identified per disease, their biological interpretation has in many cases remained elusive. To address this, we have combined GWAS results with orthogonal sources of evidence, namely the current knowledge of molecular pathways; real-world clinical data from six million patients; RNA expression across tissues from Alzheimer’s disease (AD) patients, and purpose-built rodent models for experimental validation. In more detail, first we show that when examined at a pathway level, analysis of all GWAS studies groups AD in a cluster with disorders of immunity and inflammation. Using clinical data, we show that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the Janus kinases/signal transducer and activator of transcription (JAK-STAT) pathway. Using four independent RNA expression datasets we then find evidence for the altered regulation of JAK-STAT pathway genes in AD. Finally, we use both in vitro and in vivo rodent models to demonstrate that Aβ induces gene expression of the key drivers of this pathway, providing experimental evidence to validate these data-driven observations. These results therefore nominate JAK-STAT anomalies as a prominent aetiopathological event in AD and hence a potential target for therapeutic development, and moreover demonstrate a de novo multi-modal approach to derive information from rapidly increasing genomic datasets. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Review

Jump to: Research

Open AccessReview
Calcium, Bioenergetics, and Parkinson’s Disease
Cells 2020, 9(9), 2045; https://doi.org/10.3390/cells9092045 - 08 Sep 2020
Cited by 1
Abstract
Degeneration of substantia nigra (SN) dopaminergic (DAergic) neurons is responsible for the core motor deficits of Parkinson’s disease (PD). These neurons are autonomous pacemakers that have large cytosolic Ca2+ oscillations that have been linked to basal mitochondrial oxidant stress and turnover. This [...] Read more.
Degeneration of substantia nigra (SN) dopaminergic (DAergic) neurons is responsible for the core motor deficits of Parkinson’s disease (PD). These neurons are autonomous pacemakers that have large cytosolic Ca2+ oscillations that have been linked to basal mitochondrial oxidant stress and turnover. This review explores the origin of Ca2+ oscillations and their role in the control of mitochondrial respiration, bioenergetics, and mitochondrial oxidant stress. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessReview
Role of EGFR in the Nervous System
Cells 2020, 9(8), 1887; https://doi.org/10.3390/cells9081887 - 12 Aug 2020
Cited by 3
Abstract
Epidermal growth factor receptor (EGFR) is the first discovered member of the receptor tyrosine kinase superfamily and plays a fundamental role during embryogenesis and in adult tissues, being involved in growth, differentiation, maintenance and repair of various tissues and organs. The role of [...] Read more.
Epidermal growth factor receptor (EGFR) is the first discovered member of the receptor tyrosine kinase superfamily and plays a fundamental role during embryogenesis and in adult tissues, being involved in growth, differentiation, maintenance and repair of various tissues and organs. The role of EGFR in the regulation of tissue development and homeostasis has been thoroughly investigated and it has also been demonstrated that EGFR is a driver of tumorigenesis. In the nervous system, other growth factors, and thus other receptors, are important for growth, differentiation and repair of the tissue, namely neurotrophins and neurotrophins receptors. For this reason, for a long time, the role of EGFR in the nervous system has been underestimated and poorly investigated. However, EGFR is expressed both in the central and peripheral nervous systems and it has been demonstrated to have specific important neurotrophic functions, in particular in the central nervous system. This review discusses the role of EGFR in regulating differentiation and functions of neurons and neuroglia. Furthermore, its involvement in regeneration after injury and in the onset of neurodegenerative diseases is examined. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessFeature PaperReview
Signals Orchestrating Peripheral Nerve Repair
Cells 2020, 9(8), 1768; https://doi.org/10.3390/cells9081768 - 24 Jul 2020
Abstract
The peripheral nervous system has retained through evolution the capacity to repair and regenerate after assault from a variety of physical, chemical, or biological pathogens. Regeneration relies on the intrinsic abilities of peripheral neurons and on a permissive environment, and it is driven [...] Read more.
The peripheral nervous system has retained through evolution the capacity to repair and regenerate after assault from a variety of physical, chemical, or biological pathogens. Regeneration relies on the intrinsic abilities of peripheral neurons and on a permissive environment, and it is driven by an intense interplay among neurons, the glia, muscles, the basal lamina, and the immune system. Indeed, extrinsic signals from the milieu of the injury site superimpose on genetic and epigenetic mechanisms to modulate cell intrinsic programs. Here, we will review the main intrinsic and extrinsic mechanisms allowing severed peripheral axons to re-grow, and discuss some alarm mediators and pro-regenerative molecules and pathways involved in the process, highlighting the role of Schwann cells as central hubs coordinating multiple signals. A particular focus will be provided on regeneration at the neuromuscular junction, an ideal model system whose manipulation can contribute to the identification of crucial mediators of nerve re-growth. A brief overview on regeneration at sensory terminals is also included. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessReview
Emerging Roles of Inhibitor of Differentiation-1 in Alzheimer’s Disease: Cell Cycle Reentry and Beyond
Cells 2020, 9(7), 1746; https://doi.org/10.3390/cells9071746 - 21 Jul 2020
Abstract
Inhibitor of DNA-binding/differentiation (Id) proteins, a family of helix-loop-helix (HLH) proteins that includes four members of Id1 to Id4 in mammalian cells, are critical for regulating cell growth, differentiation, senescence, cell cycle progression, and increasing angiogenesis and vasculogenesis, as well as accelerating the [...] Read more.
Inhibitor of DNA-binding/differentiation (Id) proteins, a family of helix-loop-helix (HLH) proteins that includes four members of Id1 to Id4 in mammalian cells, are critical for regulating cell growth, differentiation, senescence, cell cycle progression, and increasing angiogenesis and vasculogenesis, as well as accelerating the ability of cell migration. Alzheimer’s disease (AD), the most common neurodegenerative disease in the adult population, manifests the signs of cognitive decline, behavioral changes, and functional impairment. The underlying mechanisms for AD are not well-clarified yet, but the aggregation of amyloid-beta peptides (Aβs), the major components in the senile plaques observed in AD brains, contributes significantly to the disease progression. Emerging evidence reveals that aberrant cell cycle reentry may play a central role in Aβ-induced neuronal demise. Recently, we have shown that several signaling mediators, including Id1, hypoxia-inducible factor-1 (HIF-1), cyclin-dependent kinases-5 (CDK5), and sonic hedgehog (Shh), may contribute to Aβ-induced cell cycle reentry in postmitotic neurons; furthermore, Id1 and CDK5/p25 mutually antagonize the expression/activity of each other. Therefore, Id proteins may potentially have clinical applications in AD. In this review article, we introduce the underlying mechanisms for cell cycle dysregulation in AD and present some examples, including our own studies, to show different aspects of Id1 in terms of cell cycle reentry and other signaling that may be crucial to alter the neuronal fates in this devastating neurodegenerative disease. A thorough understanding of the underlying mechanisms may provide a rationale to make an earlier intervention before the occurrence of cell cycle reentry and subsequent apoptosis in the fully differentiated neurons during the progression of AD or other neurodegenerative diseases. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessReview
G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits
Cells 2020, 9(2), 506; https://doi.org/10.3390/cells9020506 - 23 Feb 2020
Cited by 4
Abstract
Neurodegenerative diseases are a large group of neurological disorders with diverse etiological and pathological phenomena. However, current therapeutics rely mostly on symptomatic relief while failing to target the underlying disease pathobiology. G-protein-coupled receptors (GPCRs) are one of the most frequently targeted receptors for [...] Read more.
Neurodegenerative diseases are a large group of neurological disorders with diverse etiological and pathological phenomena. However, current therapeutics rely mostly on symptomatic relief while failing to target the underlying disease pathobiology. G-protein-coupled receptors (GPCRs) are one of the most frequently targeted receptors for developing novel therapeutics for central nervous system (CNS) disorders. Many currently available antipsychotic therapeutics also act as either antagonists or agonists of different GPCRs. Therefore, GPCR-based drug development is spreading widely to regulate neurodegeneration and associated cognitive deficits through the modulation of canonical and noncanonical signals. Here, GPCRs’ role in the pathophysiology of different neurodegenerative disease progressions and cognitive deficits has been highlighted, and an emphasis has been placed on the current pharmacological developments with GPCRs to provide an insight into a potential therapeutic target in the treatment of neurodegeneration. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessReview
The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models
Cells 2020, 9(1), 204; https://doi.org/10.3390/cells9010204 - 14 Jan 2020
Cited by 9
Abstract
Ca2+ is a ubiquitous second messenger that plays an essential role in physiological processes such as muscle contraction, neuronal secretion, and cell proliferation or differentiation. There is ample evidence that the dysregulation of Ca2+ signaling is one of the key events [...] Read more.
Ca2+ is a ubiquitous second messenger that plays an essential role in physiological processes such as muscle contraction, neuronal secretion, and cell proliferation or differentiation. There is ample evidence that the dysregulation of Ca2+ signaling is one of the key events in the development of neurodegenerative processes, an idea called the “calcium hypothesis” of neurodegeneration. Caenorhabditis elegans (C. elegans) is a very good model for the study of aging and neurodegeneration. In fact, many of the signaling pathways involved in longevity were first discovered in this nematode, and many models of neurodegenerative diseases have also been developed therein, either through mutations in the worm genome or by expressing human proteins involved in neurodegeneration (β-amyloid, α-synuclein, polyglutamine, or others) in defined worm tissues. The worm is completely transparent throughout its whole life, which makes it possible to carry out Ca2+ dynamics studies in vivo at any time, by expressing Ca2+ fluorescent probes in defined worm tissues, and even in specific organelles such as mitochondria. This review will summarize the evidence obtained using this model organism to understand the role of Ca2+ signaling in aging and neurodegeneration. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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