scholarly journals Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

2021 ◽  
Author(s):  
Lynn van Olst ◽  
Carla Rodriguez-Mogeda ◽  
Carmen Picon ◽  
Svenja Kiljan ◽  
Rachel E. James ◽  
...  
Keyword(s):  
Animal Model ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Activation Markers ◽  
Post Induction ◽  
Meningeal Inflammation ◽  
Neuronal Cell Bodies ◽  
Neuronal Soma ◽  
Cortical Pathology

AbstractMeningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, thereby contributing significantly to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. By extensive analysis of cortical microglia in post-mortem progressive MS tissue, we identified cortical areas with two MS-specific microglial populations, termed MS1 and MS2 cortex. The microglial population in MS1 cortex was characterized by a higher density and increased expression of the activation markers HLA class II and CD68, whereas microglia in MS2 cortex showed increased morphological complexity and loss of P2Y12 and TMEM119 expression. Interestingly, both populations associated with inflammation of the overlying meninges and were time-dependently replicated in an in vivo rat model for progressive MS-like chronic meningeal inflammation. In this recently developed animal model, cortical microglia at 1-month post-induction of experimental meningeal inflammation resembled microglia in MS1 cortex, and microglia at 2 months post-induction acquired a MS2-like phenotype. Furthermore, we observed that MS1 microglia in both MS cortex and the animal model were found closely apposing neuronal cell bodies and to mediate pre-synaptic displacement and phagocytosis, which coincided with a relative sparing of neurons. In contrast, microglia in MS2 cortex were not involved in these synaptic alterations, but instead associated with substantial neuronal loss. Taken together, our results show that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Furthermore, our in vivo data suggests that microglia initially protect neurons from meningeal inflammation-induced cell death by removing pre-synapses from the neuronal soma, but eventually lose these protective properties contributing to neuronal loss.

scholarly journals Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

2020 ◽  
Author(s):  
Lynn van Olst ◽  
Carla Rodriguez-Mogeda ◽  
Carmen Picon-Munoz ◽  
Svenja Kiljan ◽  
Rachel E. James ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neuronal Loss ◽  
Post Mortem ◽  
Protective Properties ◽  
Phenotypic Changes ◽  
Extensive Analysis ◽  
Meningeal Inflammation ◽  
Cortical Pathology ◽  
Over Time

AbstractMeningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, contributing to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. Using extensive analysis of human post-mortem tissue, we identified two distinct microglial phenotypes, termed MS1 and MS2, in the cortex of progressive MS patients. These phenotypes differed in morphology and protein expression, but both associated with inflammation of the overlying meninges. We could replicate the MS-specific microglial phenotypes in a novel in vivo rat model for progressive MS-like meningeal inflammation, with microglia present at 1 month post-induction resembling MS1 microglia whereas those at 2 months acquired an MS2-like phenotype. Interestingly, MS1 microglia were involved in presynaptic displacement and phagocytosis and associated with a relative sparing of neurons in the MS and animal cortex. In contrast, the presence of MS2 microglia coincided with substantial neuronal loss. Taken together, we uncovered that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Our data suggests that these phenotypes occur sequentially and that microglia may lose their protective properties over time, contributing to neuronal loss.

Early innervation of the metanephric kidney

Development ◽  
1988 ◽  
Vol 104 (4) ◽  
pp. 589-599 ◽  
Author(s):  
H. Sariola ◽  
K. Holm ◽  
S. Henke-Fahle
Keyword(s):  
Primary Cultures ◽  
Neuronal Cell ◽  
Similar Distribution ◽  
Renal Tubules ◽  
Experimental Conditions ◽  
Tissue Sections ◽  
Neuronal Cell Bodies ◽  
Metanephric Kidney ◽  
Kidney Morphogenesis

During kidney differentiation, the nephrogenic mesenchyme converts into renal tubules and the ureter bud branches to form the collecting system. Here we show that in the early undifferentiated kidney rudiment there is a third cell type present. In whole-mount preparations of cultured undifferentiated metanephric kidneys, neurones can be detected by immunohistochemical means with antibodies against the neurofilament triplet, 13AA8, and against neuronal cell surface gangliosides, Q211. Clusters of neuronal cell bodies can be seen in the mesenchyme close to the ureter bud. The terminal endings of neurites are found around the mesenchymal condensates that later become kidney tubules. A similar distribution of neurites can be revealed in tissue sections of kidney grafts growing in the chicken chorioallantoic membranes. In primary cultures of the ureter bud cells, neurones are constantly present. In another report, we have shown that, in experimental conditions, neurones are involved in regulation of kidney morphogenesis. The present results raise the possibility that neurones of the metanephric kidney may have this function in vivo as well.

Ventilatory effects of kainic acid injection of the ventrolateral solitary nucleus

1982 ◽  
Vol 52 (1) ◽  
pp. 131-140 ◽  
Author(s):  
A. J. Berger ◽  
K. A. Cooney
Keyword(s):  
Kainic Acid ◽  
Minute Ventilation ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Long Term Effects ◽  
Awake State ◽  
Ventilatory Responses ◽  
Neuronal Cell Bodies ◽  
Ventilatory Effects ◽  
Kainic Acid Injection

We studied in cats the long-term effects upon resting ventilation and the ventilatory responses to CO2 breathing of destruction of neuronal cell bodies within the ventrolateral nucleus of the tractus solitarius (vl-NTS) by kainic acid (KA) injection (KAI). Animals were studied in the awake state and under pentobarbital anesthesia both before and 8 wk after stereotaxic bilateral microinjection of the vl-NTS with mock cerebrospinal fluid (CSF) (controls, n = 2) or with KA in mock CSF (KAI, n = 5). KA reduced the number of cell bodies within the vl-NTS by 75%. Under anesthesia minute ventilation (VI) was reduced by 49% after KAI, due primarily to a 54% reduction in breathing frequency (f). Four of five anesthetized KAI animals exhibited a significantly reduced (P less than 0.01) ventilatory sensitivity to inspired CO2 under anesthesia. In the awake state some KAI animals had significant changes (P less than 0.01) in ventilation; VI reduced (2 of 5), tidal volume reduced (1 of 5), f reduced (3 of 5), and inspiratory and expiratory times increased (2 of 5). Decreases in the awake ventilatory CO2 sensitivity were not significant within individual KAI animals but were significant (P less than 0.05) when considered as a group. Thus following 75% neuronal loss within the vl-NTS, rhythmic ventilation was sustained during both anesthesia and wakefulness, although f was reduced in the former state. The vl-NTS may function to set most but not all of the ventilatory sensitivity to CO2 during anesthesia and to a lesser extent during wakefulness.

scholarly journals Overexpression of Mitochondrial Calcium Uniporter Causes Neuronal Death

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Veronica Granatiero ◽  
Marco Pacifici ◽  
Anna Raffaello ◽  
Diego De Stefani ◽  
Rosario Rizzuto
Keyword(s):  
Cell Fate ◽  
Neuronal Death ◽  
Cortical Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Calcium Uniporter ◽  
Organelle Morphology

Neurodegenerative diseases are a large and heterogeneous group of disorders characterized by selective and progressive death of specific neuronal subtypes. In most of the cases, the pathophysiology is still poorly understood, although a number of hypotheses have been proposed. Among these, dysregulation of Ca2+ homeostasis and mitochondrial dysfunction represent two broadly recognized early events associated with neurodegeneration. However, a direct link between these two hypotheses can be drawn. Mitochondria actively participate to global Ca2+ signaling, and increases of [Ca2+] inside organelle matrix are known to sustain energy production to modulate apoptosis and remodel cytosolic Ca2+ waves. Most importantly, while mitochondrial Ca2+ overload has been proposed as the no-return signal, triggering apoptotic or necrotic neuronal death, until now direct evidences supporting this hypothesis, especially in vivo, are limited. Here, we took advantage of the identification of the mitochondrial Ca2+ uniporter (MCU) and tested whether mitochondrial Ca2+ signaling controls neuronal cell fate. We overexpressed MCU both in vitro, in mouse primary cortical neurons, and in vivo, through stereotaxic injection of MCU-coding adenoviral particles in the brain cortex. We first measured mitochondrial Ca2+ uptake using quantitative genetically encoded Ca2+ probes, and we observed that the overexpression of MCU causes a dramatic increase of mitochondrial Ca2+ uptake both at resting and after membrane depolarization. MCU-mediated mitochondrial Ca2+ overload causes alteration of organelle morphology and dysregulation of global Ca2+ homeostasis. Most importantly, MCU overexpression in vivo is sufficient to trigger gliosis and neuronal loss. Overall, we demonstrated that mitochondrial Ca2+ overload is per se sufficient to cause neuronal cell death both in vitro and in vivo, thus highlighting a potential key step in neurodegeneration.

scholarly journals Dual Targeting by Inhibition of Phosphoinositide-3-Kinase and Mammalian Target of Rapamycin Attenuates the Neuroinflammatory Responses in Murine Hippocampal Cells and Seizures in C57BL/6 Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Preeti Vyas ◽  
Rajkumar Tulsawani ◽  
Divya Vohora
Keyword(s):  
Cell Signaling ◽  
Day Treatment ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Ht22 Cells ◽  
Seizure Severity ◽  
Combination Model

Emerging evidence suggests the association of seizures and inflammation; however, underlying cell signaling mechanisms are still not fully understood. Overactivation of phosphoinositide-3-kinases is associated with both neuroinflammation and seizures. Herein, we speculate the PI3K/Akt/mTOR pathway as a promising therapeutic target for neuroinflammation-mediated seizures and associated neurodegeneration. Firstly, we cultured HT22 cells for detection of the downstream cell signaling events activated in a lipopolysaccharide (LPS)-primed pilocarpine (PILO) model. We then evaluated the effects of 7-day treatment of buparlisib (PI3K inhibitor, 25 mg/kg p.o.), dactolisib (PI3K/mTOR inhibitor, 25 mg/kg p.o.), and rapamycin (mTORC1 inhibitor, 10 mg/kg p.o.) in an LPS-primed PILO model of seizures in C57BL/6 mice. LPS priming resulted in enhanced seizure severity and reduced latency. Buparlisib and dactolisib, but not rapamycin, prolonged latency to seizures and reduced neuronal loss, while all drugs attenuated seizure severity. Buparlisib and dactolisib further reduced cellular redox, mitochondrial membrane potential, cleaved caspase-3 and p53, nuclear integrity, and attenuated NF-κB, IL-1β, IL-6, TNF-α, and TGF-β1 and TGF-β2 signaling both in vitro and in vivo post-PILO and LPS+PILO inductions; however, rapamycin mitigated the same only in the PILO model. Both drugs protected against neuronal cell death demonstrating the contribution of this pathway in the seizure-induced neuronal pyknosis; however, rapamycin showed resistance in a combination model. Furthermore, LPS and PILO exposure enhanced pAkt/Akt and phospho-p70S6/total-p70S6 kinase activity, while buparlisib and dactolisib, but not rapamycin, could reduce it in a combination model. Partial rapamycin resistance was observed possibly due to the reactivation of the pathway by a functionally different complex of mTOR, i.e., mTORC2. Our study substantiated the plausible involvement of PI3K-mediated apoptotic and inflammatory pathways in LPS-primed PILO-induced seizures and provides evidence that its modulation constitutes an anti-inflammatory mechanism by which seizure inhibitory effects are observed. We showed dual inhibition by dactolisib as a promising approach. Targeting this pathway at two nodes at a time may provide new avenues for antiseizure therapies.

Scanning Electron Microscopy of neuronal cell bodies isolated from the adult mammalian central nervous system

1990 ◽  
Vol 48 (3) ◽  
pp. 426-427
Author(s):  
Wenshu Liu ◽  
J. Franklin Bailey ◽  
Visaka Limwongse ◽  
Mark DeSantis
Keyword(s):  
Electron Microscopy ◽  
Scanning Electron Microscopy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuronal Cell ◽  
Female Rats ◽  
Male And Female Rats ◽  
Neuronal Cell Bodies ◽  
Neuronal Soma ◽  
Scanning Electron

Action potentials generated in a motor neuron reflect the summation of synaptic inputs it receives from other neurons. Those synapses occur at points of contiguity between the presynaptic boutons and the surface of the motor neuron. Evidence that the density of axosomalic boutons on motor neurons varies directly with the size of the motor neuronal soma is indirect. Counts of the number of boutons per unit area at the surface of the motor neuron’s cell body using scanning electron microscopy (SEM) would allow an independent, direct assessment of that inference. We describe here procedures for consistently isolating the somas of CNS neurons, specifically those associated with the adult rat’s trigeminal nerve, so that axosomatic boutons can be seen by SEM (Figures 1 and 2).Adult male and female rats were anesthetized and then perfused with saline followed by 4% paraformaldehyde. The brain stem was removed and sectioned at 200 um thickness on a vibratome. Sections containing the trigeminal motor and mesencephalic nuclei were pinned to Sylgard-lined dishes containing phosphate buffer (0.1 M, pH 7.2).

Surface-in pathology in multiple sclerosis: a new view on pathogenesis?

Brain ◽  
2021 ◽  
Author(s):  
Matteo Pardini ◽  
J William L Brown ◽  
Roberta Magliozzi ◽  
Richard Reynolds ◽  
Declan T Chard
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Grey Matter ◽  
Magnetization Transfer ◽  
Neuronal Loss ◽  
Magnetization Transfer Ratio ◽  
Supporting Evidence ◽  
Transfer Ratio ◽  
Meningeal Inflammation

Abstract While multiple sclerosis can affect any part of the CNS, it does not do so evenly. In white matter it has long been recognized that lesions tend to occur around the ventricles, and grey matter lesions mainly accrue in the outermost (subpial) cortex. In cortical grey matter, neuronal loss is greater in the outermost layers. This cortical gradient has been replicated in vivo with magnetization transfer ratio and similar gradients in grey and white matter magnetization transfer ratio are seen around the ventricles, with the most severe abnormalities abutting the ventricular surface. The cause of these gradients remains uncertain, though soluble factors released from meningeal inflammation into the CSF has the most supporting evidence. In this Update, we review this ‘surface-in’ spatial distribution of multiple sclerosis abnormalities and consider the implications for understanding pathogenic mechanisms and treatments designed to slow or stop them.

scholarly journals New oligodendrocytes exhibit more abundant and accurate myelin regeneration than those that survive demyelination

2020 ◽  
Author(s):  
Sarah A Neely ◽  
Jill M Williamson ◽  
Anna Klingseisen ◽  
Lida Zoupi ◽  
Jason J Early ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Neuronal Cell ◽  
Live Imaging ◽  
Therapeutic Strategies ◽  
Demyelinating Diseases ◽  
Neuronal Cell Bodies ◽  
The Central Nervous System

Regeneration of myelin (remyelination) in the central nervous system (CNS) has long been thought to be principally mediated by newly generated oligodendrocytes, a premise underpinning therapeutic strategies for demyelinating diseases, including multiple sclerosis (MS). Recent studies have indicated that oligodendrocytes that survive demyelination can also contribute to remyelination, including in MS, but it is unclear how remyelination by surviving oligodendrocytes compares to that of newly generated oligodendrocytes. Here we studied oligodendrocytes in MS, and also imaged remyelination in vivo by surviving and new oligodendrocytes using zebrafish. We define a previously unappreciated pathology in MS, myelination of neuronal cell bodies, which is recapitulated during remyelination by surviving oligodendrocytes in zebrafish. Live imaging also revealed that surviving oligodendrocytes make very few new sheaths, but can support sheath growth along axons. In comparison, newly made oligodendrocytes make abundant new sheaths, properly targeted to axons, and exhibit a much greater capacity for regeneration.

scholarly journals Axonal Transport as an In Vivo Biomarker for Retinal Neuropathy

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1298
Author(s):  
Lucia G. Le Roux ◽  
Xudong Qiu ◽  
Megan C. Jacobsen ◽  
Mark D. Pagel ◽  
Seth T. Gammon ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Vision Loss ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Fluorescent Imaging ◽  
Imaging Agent ◽  
Imaging Biomarker ◽  
Fast Axonal Transport

We illuminate a possible explanatory pathophysiologic mechanism for retinal cellular neuropathy by means of a novel diagnostic method using ophthalmoscopic imaging and a molecular imaging agent targeted to fast axonal transport. The retinal neuropathies are a group of diseases with damage to retinal neural elements. Retinopathies lead to blindness but are typically diagnosed late, when substantial neuronal loss and vision loss have already occurred. We devised a fluorescent imaging agent based on the non-toxic C fragment of tetanus toxin (TTc), which is taken up and transported in neurons using the highly conserved fast axonal transport mechanism. TTc serves as an imaging biomarker for normal axonal transport and demonstrates impairment of axonal transport early in the course of an N-methyl-D-aspartic acid (NMDA)-induced excitotoxic retinopathy model in rats. Transport-related imaging findings were dramatically different between normal and retinopathic eyes prior to presumed neuronal cell death. This proof-of-concept study provides justification for future clinical translation.

scholarly journals Epigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective

2019 ◽  
Author(s):  
Marshall Lee ◽  
Killinger Bryan ◽  
Li Peipei ◽  
Ensink Elizabeth ◽  
Li Katie ◽  
...  
Keyword(s):  
Immune Responses ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Genome Wide ◽  
Dopaminergic Neuronal Loss ◽  
Activation Pathways ◽  
Neuronal Functions ◽  
Novel Therapeutic ◽  
Cytosine Modification

AbstractPD pathogenesis may involve the epigenetic control of enhancers that modify neuronal functions. Here, we comprehensively profile DNA methylation at enhancers, genome-wide, in neurons of 57 PD patients and 48 control individuals. We found a widespread increase in cytosine modifications at enhancers in PD neurons, which is partly explained by elevated hydroxymethylation levels. Epigenetic dysregulation of enhancers in PD converge on transcriptional abnormalities affecting neuronal signaling and immune activation pathways. In particular, PD patients exhibit an epigenetic and transcriptional upregulation of TET2, a master-regulator of cytosine modification status. TET2 inactivation in a neuronal cell line results in cytosine modification changes that are reciprocal to those observed in PD neurons. Furthermore, Tet2 inactivation in mice fully prevents dopaminergic neuronal loss in the substantia nigra induced by prior inflammation. Tet2 loss in mice also attenuates transcriptional immune responses to an inflammatory trigger. Thus, widespread epigenetic dysregulation of enhancers in PD neurons may, in part, be mediated by increased TET2 expression. Decreased Tet2 activity is neuroprotective, in vivo, and may be a novel therapeutic target for PD.

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