Editorial

5 pages, 213 KiB

Open AccessEditorial

Key Signalling Molecules in Aging and Neurodegeneration

by Riccardo Filadi and Paola Pizzo

Cells 2022, 11(5), 834; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11050834 - 28 Feb 2022

Cited by 1 | Viewed by 2665

One of the major challenges of modern medicine is to block or prevent the neurodegenerative processes inevitably associated with different pathological conditions [...] Full article

(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)

Research

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20 pages, 3094 KiB

Open AccessFeature PaperArticle

Effects of Mild Excitotoxic Stimulus on Mitochondria Ca²⁺ Handling in Hippocampal Cultures of a Mouse Model of Alzheimer’s Disease

by Giulia Rigotto, Lorena Zentilin, Tullio Pozzan and Emy Basso

Cells 2021, 10(8), 2046; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082046 - 10 Aug 2021

Cited by 8 | Viewed by 2560

Abstract

In Alzheimer’s disease (AD), the molecular mechanisms involved in the neurodegeneration are still incompletely defined, though this aspect is crucial for a better understanding of the malady and for devising effective therapies. Mitochondrial dysfunctions and altered Ca²⁺ signaling have long been implicated [...] Read more.

In Alzheimer’s disease (AD), the molecular mechanisms involved in the neurodegeneration are still incompletely defined, though this aspect is crucial for a better understanding of the malady and for devising effective therapies. Mitochondrial dysfunctions and altered Ca²⁺ signaling have long been implicated in AD, though it is debated whether these events occur early in the course of the pathology, or whether they develop at late stages of the disease and represent consequences of different alterations. Mitochondria are central to many aspects of cellular metabolism providing energy, lipids, reactive oxygen species, signaling molecules for cellular quality control, and actively shaping intracellular Ca²⁺ signaling, modulating the intensity and duration of the signal itself. Abnormalities in the ability of mitochondria to take up and subsequently release Ca²⁺ could lead to changes in the metabolism of the organelle, and of the cell as a whole, that eventually result in cell death. We sought to investigate the role of mitochondria and Ca²⁺ signaling in a model of Familial Alzheimer’s disease and found early alterations in mitochondria physiology under stressful condition, namely, reduced maximal respiration, decreased ability to sustain membrane potential, and a slower return to basal matrix Ca²⁺ levels after a mild excitotoxic stimulus. Treatment with an inhibitor of the permeability transition pore attenuated some of these mitochondrial disfunctions and may represent a promising tool to ameliorate mitochondria and cellular functioning in AD and prevent or slow down cell loss in the disease. Full article

(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)

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16 pages, 3157 KiB

Open AccessArticle

Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain

by Michela Rossini, Paloma García-Casas, Riccardo Filadi and Paola Pizzo

Cells 2021, 10(8), 1968; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081968 - 03 Aug 2021

Cited by 6 | Viewed by 2444

Abstract

Presenilin 2 (PS2), one of the three proteins in which mutations are linked to familial Alzheimer’s disease (FAD), exerts different functions within the cell independently of being part of the γ-secretase complex, thus unrelated to toxic amyloid peptide formation. In particular, its enrichment [...] Read more.

Presenilin 2 (PS2), one of the three proteins in which mutations are linked to familial Alzheimer’s disease (FAD), exerts different functions within the cell independently of being part of the γ-secretase complex, thus unrelated to toxic amyloid peptide formation. In particular, its enrichment in endoplasmic reticulum (ER) membrane domains close to mitochondria (i.e., mitochondria-associated membranes, MAM) enables PS2 to modulate multiple processes taking place on these signaling hubs, such as Ca²⁺ handling and lipid synthesis. Importantly, upregulated MAM function appears to be critical in AD pathogenesis. We previously showed that FAD-PS2 mutants reinforce ER–mitochondria tethering, by interfering with the activity of mitofusin 2, favoring their Ca²⁺ crosstalk. Here, we deepened the molecular mechanism underlying PS2 activity on ER–mitochondria tethering, identifying its protein loop as an essential domain to mediate the reinforced ER–mitochondria connection in FAD-PS2 models. Moreover, we introduced a novel tool, the PS2 loop domain targeted to the outer mitochondrial membrane, Mit-PS2-LOOP, that is able to counteract the activity of FAD-PS2 on organelle tethering, which possibly helps in recovering the FAD-PS2-associated cellular alterations linked to an increased organelle coupling. Full article

(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)

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23 pages, 3823 KiB

Open AccessArticle

Calcium Signaling and Mitochondrial Function in Presenilin 2 Knock-Out Mice: Looking for Any Loss-of-Function Phenotype Related to Alzheimer’s Disease

by Alice Rossi, Luisa Galla, Chiara Gomiero, Lorena Zentilin, Mauro Giacca, Valentina Giorgio, Tito Calì, Tullio Pozzan, Elisa Greotti and Paola Pizzo

Cells 2021, 10(2), 204; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020204 - 21 Jan 2021

Cited by 10 | Viewed by 3269

Abstract

Alzheimer′s disease (AD) is the most common age-related neurodegenerative disorder in which learning, memory and cognitive functions decline progressively. Familial forms of AD (FAD) are caused by mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 [...] Read more.

Alzheimer′s disease (AD) is the most common age-related neurodegenerative disorder in which learning, memory and cognitive functions decline progressively. Familial forms of AD (FAD) are caused by mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes. Presenilin 1 (PS1) and its homologue, presenilin 2 (PS2), represent, alternatively, the catalytic core of the γ-secretase complex that, by cleaving APP, produces neurotoxic amyloid beta (Aβ) peptides responsible for one of the histopathological hallmarks in AD brains, the amyloid plaques. Recently, PSEN1 FAD mutations have been associated with a loss-of-function phenotype. To investigate whether this finding can also be extended to PSEN2 FAD mutations, we studied two processes known to be modulated by PS2 and altered by FAD mutations: Ca²⁺ signaling and mitochondrial function. By exploiting neurons derived from a PSEN2 knock-out (PS2–/–) mouse model, we found that, upon IP₃-generating stimulation, cytosolic Ca²⁺ handling is not altered, compared to wild-type cells, while mitochondrial Ca²⁺ uptake is strongly compromised. Accordingly, PS2–/– neurons show a marked reduction in endoplasmic reticulum–mitochondria apposition and a slight alteration in mitochondrial respiration, whereas mitochondrial membrane potential, and organelle morphology and number appear unchanged. Thus, although some alterations in mitochondrial function appear to be shared between PS2–/– and FAD-PS2-expressing neurons, the mechanisms leading to these defects are quite distinct between the two models. Taken together, our data appear to be difficult to reconcile with the proposal that FAD-PS2 mutants are loss-of-function, whereas the concept that PS2 plays a key role in sustaining mitochondrial function is here confirmed. Full article

(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)

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21 pages, 2139 KiB

Open AccessArticle

Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models

by Nuno Santos Leal, Giacomo Dentoni, Bernadette Schreiner, Luana Naia, Antonio Piras, Caroline Graff, Antonio Cattaneo, Giovanni Meli, Maho Hamasaki, Per Nilsson and Maria Ankarcrona

Cells 2020, 9(12), 2552; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122552 - 28 Nov 2020

Cited by 38 | Viewed by 4067

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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22 pages, 3395 KiB

Open AccessFeature PaperArticle

Overexpression of α-Synuclein by Oligodendrocytes in Transgenic Mice Does Not Recapitulate the Fibrillar Aggregation Seen in Multiple System Atrophy

by Florent Laferrière, Xin He, Federica Zinghirino, Evelyne Doudnikoff, Emilie Faggiani, Wassilios G. Meissner, Erwan Bezard, Francesca De Giorgi and François Ichas

Cells 2020, 9(11), 2371; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9112371 - 29 Oct 2020

Cited by 12 | Viewed by 5332

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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18 pages, 2852 KiB

Open AccessArticle

Molecular Genetics and Functional Analysis Implicate CDKN2BAS1-CDKN2B Involvement in POAG Pathogenesis

by Sonika Rathi, Ian Danford, Harini V. Gudiseva, Lana Verkuil, Maxwell Pistilli, Sushma Vishwakarma, Inderjeet Kaur, Tarjani Vivek Dave, Joan M. O’Brien and Venkata R. M. Chavali

Cells 2020, 9(9), 1934; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9091934 - 21 Aug 2020

Cited by 10 | Viewed by 3429

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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21 pages, 2858 KiB

Open AccessArticle

Fyn Tyrosine Kinase Elicits Amyloid Precursor Protein Tyr682 Phosphorylation in Neurons from Alzheimer’s Disease Patients

by Filomena Iannuzzi, Rossana Sirabella, Nadia Canu, Thorsten J. Maier, Lucio Annunziato and Carmela Matrone

Cells 2020, 9(8), 1807; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9081807 - 30 Jul 2020

Cited by 21 | Viewed by 4519

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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14 pages, 1828 KiB

Open AccessArticle

The Pluripotency Factor Nanog Protects against Neuronal Amyloid β-Induced Toxicity and Oxidative Stress through Insulin Sensitivity Restoration

by Ching-Chi Chang, Hsin-Hua Li, Sing-Hua Tsou, Hui-Chih Hung, Guang-Yaw Liu, Tatiana A. Korolenko, Te-Jen Lai, Ying-Jui Ho and Chih-Li Lin

Cells 2020, 9(6), 1339; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9061339 - 27 May 2020

Cited by 3 | Viewed by 2822

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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13 pages, 2008 KiB

Open AccessFeature PaperArticle

Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices

by Javier Garrosa, Iñigo Paredes, Philippe Marambaud, Manuela G. López and María F. Cano-Abad

Cells 2020, 9(3), 664; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9030664 - 09 Mar 2020

Cited by 10 | Viewed by 2622

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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23 pages, 6599 KiB

Open AccessArticle

Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism

by Mathilde Chivet, Caterina Marchioretti, Marco Pirazzini, Diana Piol, Chiara Scaramuzzino, Maria Josè Polanco, Vanina Romanello, Emanuela Zuccaro, Sara Parodi, Maurizio D’Antonio, Carlo Rinaldi, Fabio Sambataro, Elena Pegoraro, Gianni Soraru, Udai Bhan Pandey, Marco Sandri, Manuela Basso and Maria Pennuto

Cells 2020, 9(2), 325; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020325 - 30 Jan 2020

Cited by 25 | Viewed by 6559

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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20 pages, 5121 KiB

Open AccessArticle

Dampened Slow Oscillation Connectivity Anticipates Amyloid Deposition in the PS2APP Mouse Model of Alzheimer’s Disease

by Alessandro Leparulo, Mufti Mahmud, Elena Scremin, Tullio Pozzan, Stefano Vassanelli and Cristina Fasolato

Cells 2020, 9(1), 54; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010054 - 24 Dec 2019

Cited by 18 | Viewed by 3414

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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13 pages, 7695 KiB

Open AccessCommunication

Involvement of the Chemokine Prokineticin-2 (PROK2) in Alzheimer’s Disease: From Animal Models to the Human Pathology

by Roberta Lattanzi, Daniela Maftei, Carla Petrella, Massimo Pieri, Giulia Sancesario, Tommaso Schirinzi, Sergio Bernardini, Christian Barbato, Massimo Ralli, Antonio Greco, Roberta Possenti, Giuseppe Sancesario and Cinzia Severini

Cells 2019, 8(11), 1430; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8111430 - 13 Nov 2019

Cited by 17 | Viewed by 3096

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 Aβ_1–42 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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19 pages, 7814 KiB

Open AccessArticle

Stromal Cell-Derived Factor 1 Protects Brain Vascular Endothelial Cells from Radiation-Induced Brain Damage

by Jong-Ik Heo, Kwang Il Kim, Sang-Keun Woo, Joong Sun Kim, Kyu Jin Choi, Hae-June Lee and Kwang Seok Kim

Cells 2019, 8(10), 1230; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8101230 - 10 Oct 2019

Cited by 11 | Viewed by 3367

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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13 pages, 2943 KiB

Open AccessCommunication

An Agonist of the CXCR4 Receptor Strongly Promotes Regeneration of Degenerated Motor Axon Terminals

by Samuele Negro, Giulia Zanetti, Andrea Mattarei, Alice Valentini, Aram Megighian, Giulia Tombesi, Alessandro Zugno, Valentina Dianin, Marco Pirazzini, Silvia Fillo, Florigio Lista, Michela Rigoni and Cesare Montecucco

Cells 2019, 8(10), 1183; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8101183 - 30 Sep 2019

Cited by 15 | Viewed by 3656

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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22 pages, 7199 KiB

Open AccessArticle

Deregulated miR-29b-3p Correlates with Tissue-Specific Activation of Intrinsic Apoptosis in An Animal Model of Amyotrophic Lateral Sclerosis

by Christina L. Klatt, Verena Theis, Stephan Hahn, Carsten Theiss and Veronika Matschke

Cells 2019, 8(9), 1077; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8091077 - 12 Sep 2019

Cited by 25 | Viewed by 4161

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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18 pages, 3950 KiB

Open AccessArticle

Free-Water Imaging in White and Gray Matter in Parkinson’s Disease

by Christina Andica, Koji Kamagata, Taku Hatano, Asami Saito, Wataru Uchida, Takashi Ogawa, Haruka Takeshige-Amano, Andrew Zalesky, Akihiko Wada, Michimasa Suzuki, Akifumi Hagiwara, Ryusuke Irie, Masaaki Hori, Kanako K. Kumamaru, Genko Oyama, Yashushi Shimo, Atsushi Umemura, Christos Pantelis, Nobutaka Hattori and Shigeki Aoki

Cells 2019, 8(8), 839; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8080839 - 05 Aug 2019

Cited by 41 | Viewed by 5482

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 (FA_T), increased FW-corrected mean, axial, and radial diffusivities (MD_T, AD_T, and RD_T, 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 FA_T and higher MD_T, AD_T, and RD_T (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 MD_T, AD_T, and FW than the controls, whereas ROI analysis showed significantly increased MD_T and FW and a trend toward increased AD_T 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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16 pages, 1494 KiB

Open AccessArticle

Isomerization of Asp7 in Beta-Amyloid Enhances Inhibition of the α7 Nicotinic Receptor and Promotes Neurotoxicity

by Evgeny P. Barykin, Alexandra I. Garifulina, Elena V. Kruykova, Ekaterina N. Spirova, Anastasia A. Anashkina, Alexei A. Adzhubei, Irina V. Shelukhina, Igor E. Kasheverov, Vladimir A. Mitkevich, Sergey A. Kozin, Michael Hollmann, Victor I. Tsetlin and Alexander A. Makarov

Cells 2019, 8(8), 771; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8080771 - 25 Jul 2019

Cited by 24 | Viewed by 4109

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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16 pages, 4027 KiB

Open AccessArticle

Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles

by Vanina Romanello, Marco Scalabrin, Mattia Albiero, Bert Blaauw, Luca Scorrano and Marco Sandri

Cells 2019, 8(6), 597; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8060597 - 15 Jun 2019

Cited by 57 | Viewed by 6324

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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25 pages, 10202 KiB

Open AccessArticle

pHluorin-BACE1-mCherry Acts as a Reporter for the Intracellular Distribution of Active BACE1 In Vitro and In Vivo

by Lu Zhao, Yang Zhao, Fu-Lei Tang, Lei Xiong, Ce Su, Lin Mei, Xiao-Juan Zhu and Wen-Cheng Xiong

Cells 2019, 8(5), 474; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050474 - 17 May 2019

Cited by 7 | Viewed by 7231

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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17 pages, 1608 KiB

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

by Alejo J. Nevado-Holgado, Elena Ribe, Laura Thei, Laura Furlong, Miguel-Angel Mayer, Jie Quan, Jill C. Richardson, Jonathan Cavanagh, NIMA Consortium and Simon Lovestone

Cells 2019, 8(5), 425; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050425 - 08 May 2019

Cited by 25 | Viewed by 5592

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: Editorial, Research

18 pages, 449 KiB

Open AccessReview

Lighting Up Ca²⁺ Dynamics in Animal Models

by Nelly Redolfi, Paloma García-Casas, Chiara Fornetto, Sonia Sonda, Paola Pizzo and Diana Pendin

Cells 2021, 10(8), 2133; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082133 - 19 Aug 2021

Cited by 6 | Viewed by 2747

Abstract

Calcium (Ca²⁺) signaling coordinates are crucial processes in brain physiology. Particularly, fundamental aspects of neuronal function such as synaptic transmission and neuronal plasticity are regulated by Ca²⁺, and neuronal survival itself relies on Ca²⁺-dependent cascades. Indeed, impaired [...] Read more.

Calcium (Ca²⁺) signaling coordinates are crucial processes in brain physiology. Particularly, fundamental aspects of neuronal function such as synaptic transmission and neuronal plasticity are regulated by Ca²⁺, and neuronal survival itself relies on Ca²⁺-dependent cascades. Indeed, impaired Ca²⁺ homeostasis has been reported in aging as well as in the onset and progression of neurodegeneration. Understanding the physiology of brain function and the key processes leading to its derangement is a core challenge for neuroscience. In this context, Ca²⁺ imaging represents a powerful tool, effectively fostered by the continuous amelioration of Ca²⁺ sensors in parallel with the improvement of imaging instrumentation. In this review, we explore the potentiality of the most used animal models employed for Ca²⁺ imaging, highlighting their application in brain research to explore the pathogenesis of neurodegenerative diseases. Full article

(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)

31 pages, 1434 KiB

Open AccessReview

Compartmentalized Signaling in Aging and Neurodegeneration

by Giulietta Di Benedetto, Liliana F. Iannucci, Nicoletta C. Surdo, Sofia Zanin, Filippo Conca, Francesca Grisan, Andrea Gerbino and Konstantinos Lefkimmiatis

Cells 2021, 10(2), 464; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020464 - 22 Feb 2021

Cited by 16 | Viewed by 3741

Abstract

The cyclic AMP (cAMP) signalling cascade is necessary for cell homeostasis and plays important roles in many processes. This is particularly relevant during ageing and age-related diseases, where drastic changes, generally decreases, in cAMP levels have been associated with the progressive decline in [...] Read more.

The cyclic AMP (cAMP) signalling cascade is necessary for cell homeostasis and plays important roles in many processes. This is particularly relevant during ageing and age-related diseases, where drastic changes, generally decreases, in cAMP levels have been associated with the progressive decline in overall cell function and, eventually, the loss of cellular integrity. The functional relevance of reduced cAMP is clearly supported by the finding that increases in cAMP levels can reverse some of the effects of ageing. Nevertheless, despite these observations, the molecular mechanisms underlying the dysregulation of cAMP signalling in ageing are not well understood. Compartmentalization is widely accepted as the modality through which cAMP achieves its functional specificity; therefore, it is important to understand whether and how this mechanism is affected during ageing and to define which is its contribution to this process. Several animal models demonstrate the importance of specific cAMP signalling components in ageing, however, how age-related changes in each of these elements affect the compartmentalization of the cAMP pathway is largely unknown. In this review, we explore the connection of single components of the cAMP signalling cascade to ageing and age-related diseases whilst elaborating the literature in the context of cAMP signalling compartmentalization. Full article

(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)

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21 pages, 440 KiB

Open AccessReview

Endogenous Mechanisms of Neuroprotection: To Boost or Not to Be

by Sara Marmolejo-Martínez-Artesero, Caty Casas and David Romeo-Guitart

Cells 2021, 10(2), 370; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020370 - 10 Feb 2021

Cited by 11 | Viewed by 3021

Abstract

Postmitotic cells, like neurons, must live through a lifetime. For this reason, organisms/cells have evolved with self-repair mechanisms that allow them to have a long life. The discovery workflow of neuroprotectors during the last years has focused on blocking the pathophysiological mechanisms that [...] Read more.

Postmitotic cells, like neurons, must live through a lifetime. For this reason, organisms/cells have evolved with self-repair mechanisms that allow them to have a long life. The discovery workflow of neuroprotectors during the last years has focused on blocking the pathophysiological mechanisms that lead to neuronal loss in neurodegeneration. Unfortunately, only a few strategies from these studies were able to slow down or prevent neurodegeneration. There is compelling evidence demonstrating that endorsing the self-healing mechanisms that organisms/cells endogenously have, commonly referred to as cellular resilience, can arm neurons and promote their self-healing. Although enhancing these mechanisms has not yet received sufficient attention, these pathways open up new therapeutic avenues to prevent neuronal death and ameliorate neurodegeneration. Here, we highlight the main endogenous mechanisms of protection and describe their role in promoting neuron survival during neurodegeneration. Full article

(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)

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32 pages, 1337 KiB

Open AccessReview

Calcium, Bioenergetics, and Parkinson’s Disease

by Enrico Zampese and D. James Surmeier

Cells 2020, 9(9), 2045; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9092045 - 08 Sep 2020

Cited by 39 | Viewed by 5831

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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27 pages, 2642 KiB

Open AccessReview

Role of EGFR in the Nervous System

by Roberta Romano and Cecilia Bucci

Cells 2020, 9(8), 1887; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9081887 - 12 Aug 2020

Cited by 81 | Viewed by 8260

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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20 pages, 1356 KiB

Open AccessFeature PaperReview

Signals Orchestrating Peripheral Nerve Repair

by Michela Rigoni and Samuele Negro

Cells 2020, 9(8), 1768; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9081768 - 24 Jul 2020

Cited by 29 | Viewed by 4436

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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15 pages, 906 KiB

Open AccessReview

Emerging Roles of Inhibitor of Differentiation-1 in Alzheimer’s Disease: Cell Cycle Reentry and Beyond

by Shang-Der Chen, Jenq-Lin Yang, Yi-Chun Lin, A-Ching Chao and Ding-I Yang

Cells 2020, 9(7), 1746; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9071746 - 21 Jul 2020

Cited by 16 | Viewed by 3920

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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28 pages, 810 KiB

Open AccessReview

G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

by Shofiul Azam, Md. Ezazul Haque, Md. Jakaria, Song-Hee Jo, In-Su Kim and Dong-Kug Choi

Cells 2020, 9(2), 506; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020506 - 23 Feb 2020

Cited by 51 | Viewed by 11327

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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19 pages, 746 KiB

Open AccessReview

The Role of Ca²⁺ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models

by Javier Alvarez, Pilar Alvarez-Illera, Paloma García-Casas, Rosalba I. Fonteriz and Mayte Montero

Cells 2020, 9(1), 204; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010204 - 14 Jan 2020

Cited by 30 | Viewed by 5446

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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