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14 pages, 1334 KiB

Open AccessArticle

Biphasic Response of Astrocytic Brain-Derived Neurotrophic Factor Expression following Corticosterone Stimulation

by Alexandros Tsimpolis, Maria Kokkali, Aris Logothetis, Konstantinos Kalafatakis and Ioannis Charalampopoulos

Biomolecules 2022, 12(9), 1322; https://doi.org/10.3390/biom12091322 - 18 Sep 2022

Cited by 2 | Viewed by 2522

Abstract

Novel research studies indicate multivarious interactions of glucocorticoid hormones (GCs) with the brain-derived neurotrophic factor (BDNF), regulating important aspects of neuronal cell physiology. While there is recent evidence of the chronic effects of GC stimulation on BDNF levels, as well as of the [...] Read more.

Novel research studies indicate multivarious interactions of glucocorticoid hormones (GCs) with the brain-derived neurotrophic factor (BDNF), regulating important aspects of neuronal cell physiology. While there is recent evidence of the chronic effects of GC stimulation on BDNF levels, as well as of the role of BDNF stimulation in the type of genomic effects following activation of GC-sensitive receptors, no data exist concerning the acute effects of GC stimulation on BDNF/TrkB gene expression. To address this question, we conducted a chrono-pharmacological study on rodent glial cells, astrocytes, which express the BDNF receptor, TrkB, following corticosterone administration. mRNA levels of BDNF and TrkB were estimated 1, 6, 12 and 24 h post-treatment. Selective inhibitors for GC-sensitive receptors and TrkB were used to decipher the molecular pathways of the effects observed. Our data support a biphasic response of BDNF expression after corticosterone stimulation. This response is characterized by a rapid TrkB phosphorylation-dependent upregulation of BDNF mRNA within the first hour, followed by a glucocorticoid receptor (GR)-dependent downregulation of BDNF mRNA, evident at 6, 12 and 24 h, with a direct impact on the protein levels of mature BDNF. Finally, a second pulse of corticosterone administration 1 h prior to the 6, 12 or 24 h timepoints normalized BDNF expression for the corresponding timepoint (i.e., mRNA levels became indifferent from baseline). These results present for the first time a biphasic regulation of the neurotrophin system based on glucocorticoid rhythmicity, further indicating complex trophic responses to temporal hormonal mechanisms in the brain microenvironment. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neuroinflammation)

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14 pages, 1965 KiB

Open AccessFeature PaperArticle

Microglia Contributes to BAF-312 Effects on Blood–Brain Barrier Stability

by Simona Federica Spampinato, Giuseppe Costantino, Sara Merlo, Pier Luigi Canonico and Maria Angela Sortino

Biomolecules 2022, 12(9), 1174; https://doi.org/10.3390/biom12091174 - 25 Aug 2022

Cited by 11 | Viewed by 3280

Abstract

Microglia, together with astrocytes and pericytes, cooperate to ensure blood–brain barrier (BBB) stability, modulating endothelial responses to inflammatory insults. Agonists of the sphingosine 1 phosphate (S1P) receptors, such as siponimod (BAF-312), are important pharmacological tools in multiple sclerosis and other inflammatory diseases. Modulation [...] Read more.

Microglia, together with astrocytes and pericytes, cooperate to ensure blood–brain barrier (BBB) stability, modulating endothelial responses to inflammatory insults. Agonists of the sphingosine 1 phosphate (S1P) receptors, such as siponimod (BAF-312), are important pharmacological tools in multiple sclerosis and other inflammatory diseases. Modulation of S1P receptors may result in a reduced inflammatory response and increased BBB stability. An in vitro BBB model was reproduced using human-derived endothelial cells, astrocytes and microglia. Co-cultures were exposed to inflammatory cytokines (TNFα, 10 UI and IFNγ, 5 UI) in the presence of BAF-312 (100 nM), and the BBB properties and microglia role were evaluated. The drug facilitated microglial migration towards endothelial/astrocyte co-cultures, involving the activity of the metalloprotease 2 (MMP2). Microglia actively cooperated with astrocytes in the maintenance of endothelial barrier stability: in the triple co-culture, selective treatment of microglial cells with BAF-312 significantly prevented cytokines’ effects on the endothelial barrier. In conclusion, BAF-312, modulating S1P receptors in microglia, may contribute to the reinforcement of the endothelial barrier at the BBB, suggesting an additional effect of the drug in the treatment of multiple sclerosis. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neuroinflammation)

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22 pages, 4373 KiB

Open AccessArticle

ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses

by Canelif Yilmaz, Thanasis Rogdakis, Alessia Latorrata, Evangelia Thanou, Eleftheria Karadima, Eleni Papadimitriou, Eleni Siapi, Ka Wan Li, Theodora Katsila, Theodora Calogeropoulou, Ioannis Charalampopoulos and Vasileia Ismini Alexaki

Biomolecules 2022, 12(3), 424; https://doi.org/10.3390/biom12030424 - 9 Mar 2022

Cited by 4 | Viewed by 4200

Abstract

Tackling neurodegeneration and neuroinflammation is particularly challenging due to the complexity of central nervous system (CNS) disorders, as well as the limited drug accessibility to the brain. The activation of tropomyosin-related kinase A (TRKA) receptor signaling by the nerve growth factor (NGF) or [...] Read more.

Tackling neurodegeneration and neuroinflammation is particularly challenging due to the complexity of central nervous system (CNS) disorders, as well as the limited drug accessibility to the brain. The activation of tropomyosin-related kinase A (TRKA) receptor signaling by the nerve growth factor (NGF) or the neurosteroid dehydroepiandrosterone (DHEA) may combat neurodegeneration and regulate microglial function. In the present study, we synthesized a C-17-spiro-cyclopropyl DHEA derivative (ENT-A010), which was capable of activating TRKA. ENT-A010 protected PC12 cells against serum starvation-induced cell death, dorsal root ganglia (DRG) neurons against NGF deprivation-induced apoptosis and hippocampal neurons against Aβ-induced apoptosis. In addition, ENT-A010 pretreatment partially restored homeostatic features of microglia in the hippocampus of lipopolysaccharide (LPS)-treated mice, enhanced Aβ phagocytosis, and increased Ngf expression in microglia in vitro. In conclusion, the small molecule ENT-A010 elicited neuroprotective effects and modulated microglial function, thereby emerging as an interesting compound, which merits further study in the treatment of CNS disorders. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neuroinflammation)

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19 pages, 5162 KiB

Open AccessArticle

RTP801/REDD1 Is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease

by Leticia Pérez-Sisqués, Júlia Solana-Balaguer, Genís Campoy-Campos, Núria Martín-Flores, Anna Sancho-Balsells, Marcel Vives-Isern, Ferran Soler-Palazón, Marta Garcia-Forn, Mercè Masana, Jordi Alberch, Esther Pérez-Navarro, Albert Giralt and Cristina Malagelada

Biomolecules 2022, 12(1), 34; https://doi.org/10.3390/biom12010034 - 27 Dec 2021

Cited by 7 | Viewed by 4325

Abstract

RTP801/REDD1 is a stress-regulated protein whose levels are increased in several neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases (HD). RTP801 downregulation ameliorates behavioral abnormalities in several mouse models of these disorders. In HD, RTP801 mediates mutant huntingtin (mhtt) toxicity in in [...] Read more.

RTP801/REDD1 is a stress-regulated protein whose levels are increased in several neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases (HD). RTP801 downregulation ameliorates behavioral abnormalities in several mouse models of these disorders. In HD, RTP801 mediates mutant huntingtin (mhtt) toxicity in in vitro models and its levels are increased in human iPSCs, human postmortem putamen samples, and in striatal synaptosomes from mouse models of the disease. Here, we investigated the role of RTP801 in the hippocampal pathophysiology of HD. We found that RTP801 levels are increased in the hippocampus of HD patients in correlation with gliosis markers. Although RTP801 expression is not altered in the hippocampus of the R6/1 mouse model of HD, neuronal RTP801 silencing in the dorsal hippocampus with shRNA containing AAV particles ameliorates cognitive alterations. This recovery is associated with a partial rescue of synaptic markers and with a reduction in inflammatory events, especially microgliosis. Altogether, our results indicate that RTP801 could be a marker of hippocampal neuroinflammation in HD patients and a promising therapeutic target of the disease. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neuroinflammation)

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Review

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17 pages, 1137 KiB

Open AccessReview

Cerebral Glutamate Regulation and Receptor Changes in Perioperative Neuroinflammation and Cognitive Dysfunction

by Yan Zhang, John-Man-Tak Chu and Gordon-Tin-Chun Wong

Biomolecules 2022, 12(4), 597; https://doi.org/10.3390/biom12040597 - 18 Apr 2022

Cited by 50 | Viewed by 5766

Abstract

Glutamate is the major excitatory neurotransmitter in the central nervous system and is intricately linked to learning and memory. Its activity depends on the expression of AMPA and NMDA receptors and excitatory amino transporters on neurons and glial cells. Glutamate transporters prevent the [...] Read more.

Glutamate is the major excitatory neurotransmitter in the central nervous system and is intricately linked to learning and memory. Its activity depends on the expression of AMPA and NMDA receptors and excitatory amino transporters on neurons and glial cells. Glutamate transporters prevent the excess accumulation of glutamate in synapses, which can lead to aberrant synaptic signaling, excitotoxicity, or cell death. Neuroinflammation can occur acutely after surgical trauma and contributes to the development of perioperative neurocognitive disorders, which are characterized by impairment in multiple cognitive domains. In this review, we aim to examine how glutamate handling and glutamatergic function are affected by neuroinflammation and their contribution to cognitive impairment. We will first summarize the current data regarding glutamate in neurotransmission, its receptors, and their regulation and trafficking. We will then examine the impact of inflammation on glutamate handling and neurotransmission, focusing on changes in glial cells and the effect of cytokines. Finally, we will discuss these changes in the context of perioperative neuroinflammation and the implications they have for perioperative neurocognitive disorders. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neuroinflammation)

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21 pages, 1857 KiB

Open AccessEditor’s ChoiceReview

New Insights into the Role of Cysteine Cathepsins in Neuroinflammation

by Anja Pišlar, Lara Bolčina and Janko Kos

Biomolecules 2021, 11(12), 1796; https://doi.org/10.3390/biom11121796 - 30 Nov 2021

Cited by 14 | Viewed by 3860

Abstract

Neuroinflammation, which is mediated by microglia and astrocytes, is associated with the progression of neurodegenerative diseases. Increasing evidence shows that activated microglia induce the expression and secretion of various lysosomal cathepsins, particularly during the early stage of neuroinflammation. This trigger signaling cascade that [...] Read more.

Neuroinflammation, which is mediated by microglia and astrocytes, is associated with the progression of neurodegenerative diseases. Increasing evidence shows that activated microglia induce the expression and secretion of various lysosomal cathepsins, particularly during the early stage of neuroinflammation. This trigger signaling cascade that aggravate neurodegeneration. To date, most research on neuroinflammation has focused on the role of cysteine cathepsins, the largest cathepsin family. Cysteine cathepsins are primarily responsible for protein degradation in lysosomes; however, they also play a role in regulating a number of other important physiological and pathological processes. This review focuses on the functional roles of cysteine cathepsins in the central nervous system during neuroinflammation, with an emphasis on their roles in the polarization of microglia and neuroinflammation signaling, which in turn causes neuronal death and thus neurodegeneration. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neuroinflammation)

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19 pages, 1784 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial Dysfunction, Protein Misfolding and Neuroinflammation in Parkinson’s Disease: Roads to Biomarker Discovery

by Anna Picca, Flora Guerra, Riccardo Calvani, Roberta Romano, Hélio José Coelho-Júnior, Cecilia Bucci and Emanuele Marzetti

Biomolecules 2021, 11(10), 1508; https://doi.org/10.3390/biom11101508 - 13 Oct 2021

Cited by 84 | Viewed by 9870

Abstract

Parkinson’s Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational [...] Read more.

Parkinson’s Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neuroinflammation)

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20 pages, 1102 KiB

Open AccessEditor’s ChoiceReview

Oligodendrocytes and Microglia: Key Players in Myelin Development, Damage and Repair

by Ilias Kalafatakis and Domna Karagogeos

Biomolecules 2021, 11(7), 1058; https://doi.org/10.3390/biom11071058 - 20 Jul 2021

Cited by 66 | Viewed by 12558

Abstract

Oligodendrocytes, the myelin-making cells of the CNS, regulate the complex process of myelination under physiological and pathological conditions, significantly aided by other glial cell types such as microglia, the brain-resident, macrophage-like innate immune cells. In this review, we summarize how oligodendrocytes orchestrate myelination, [...] Read more.

Oligodendrocytes, the myelin-making cells of the CNS, regulate the complex process of myelination under physiological and pathological conditions, significantly aided by other glial cell types such as microglia, the brain-resident, macrophage-like innate immune cells. In this review, we summarize how oligodendrocytes orchestrate myelination, and especially myelin repair after damage, and present novel aspects of oligodendroglial functions. We emphasize the contribution of microglia in the generation and regeneration of myelin by discussing their beneficial and detrimental roles, especially in remyelination, underlining the cellular and molecular components involved. Finally, we present recent findings towards human stem cell-derived preclinical models for the study of microglia in human pathologies and on the role of microbiome on glial cell functions. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neuroinflammation)

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