scholarly journals Microglial SIRPα regulates the emergence of CD11c+ microglia and demyelination damage in white matter

2018 ◽  
Author(s):  
Miho Sato-Hashimoto ◽  
Tomomi Nozu ◽  
Riho Toriba ◽  
Ayano Horikoshi ◽  
Miho Akaike ◽  
...  
Keyword(s):  
White Matter ◽  
Membrane Protein ◽  
Functional Role ◽  
Regulatory Protein ◽  
Genetic Ablation ◽  
Brain White Matter ◽  
Expression Of Genes ◽  
The Brain ◽  
Repair Phase

AbstractA characteristic subset of microglia expressing CD11c appears in response to brain damage. However, the functional role of CD11c+ microglia, as well as the mechanism of its induction, are poorly understood. Here we report that the genetic ablation of signal regulatory protein α (SIRPα), a membrane protein, induced CD11c+ microglia in the brain white matter. Mice lacking CD47, a physiological ligand of SIRPα, and microglia-specific SIRPα knockout mice exhibited the same phenotype, suggesting the interaction between microglial SIRPα and CD47 on neighbouring cells suppressed the emergence of CD11c+ microglia. A lack of SIRPα did not cause detectable damage in the white matter, but resulted in the increased expression of genes characteristic of the repair phase after demyelination. In addition, cuprizone-induced demyelination was alleviated by the microglia-specific ablation of SIRPα. Thus, microglial SIRPα suppresses the induction of CD11c+ microglia that have the potential to accelerate the repair of damaged white matter.

scholarly journals Microglial SIRPα regulates the emergence of CD11c+ microglia and demyelination damage in white matter

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Miho Sato-Hashimoto ◽  
Tomomi Nozu ◽  
Riho Toriba ◽  
Ayano Horikoshi ◽  
Miho Akaike ◽  
...  
Keyword(s):  
White Matter ◽  
Membrane Protein ◽  
Functional Role ◽  
Regulatory Protein ◽  
Genetic Ablation ◽  
Brain White Matter ◽  
Expression Of Genes ◽  
The Brain ◽  
Repair Phase

A characteristic subset of microglia expressing CD11c appears in response to brain damage. However, the functional role of CD11c+ microglia, as well as the mechanism of its induction, are poorly understood. Here we report that the genetic ablation of signal regulatory protein α (SIRPα), a membrane protein, induced the emergence of CD11c+ microglia in the brain white matter. Mice lacking CD47, a physiological ligand of SIRPα, and microglia-specific SIRPα-knockout mice exhibited the same phenotype, suggesting that an interaction between microglial SIRPα and CD47 on neighbouring cells suppressed the emergence of CD11c+ microglia. A lack of SIRPα did not cause detectable damage to the white matter, but resulted in the increased expression of genes whose expression is characteristic of the repair phase after demyelination. In addition, cuprizone-induced demyelination was alleviated by the microglia-specific ablation of SIRPα. Thus, microglial SIRPα suppresses the induction of CD11c+ microglia that have the potential to accelerate the repair of damaged white matter.

scholarly journals Urinary ketone body loss leads to degeneration of brain white matter in elderly SLC5A8-deficient mice

2019 ◽  
Vol 40 (8) ◽  
pp. 1709-1723 ◽  
Author(s):  
Laurent Suissa ◽  
Virginie Flachon ◽  
Jean-Marie Guigonis ◽  
Charles-Vivien Olivieri ◽  
Fanny Burel-Vandenbos ◽  
...  
Keyword(s):  
White Matter ◽  
Single Photon ◽  
Photon Emission ◽  
Brain White Matter ◽  
Single Photon Emission Ct ◽  
Altered Glucose ◽  
Intramyelinic Oedema ◽  
The Brain ◽  
Deficient Mice

SLC5A8 is a sodium-coupled monocarboxylate and ketone transporter expressed in various epithelial cells. A putative role of SLC5A8 in neuroenergetics has been also hypothesized. To clarify this issue, we studied the cerebral phenotype of SLC5A8-deficient mice during aging. Elderly SLC5A8-deficient mice presented diffuse leukoencephalopathy characterized by intramyelinic oedema without demyelination suggesting chronic energetic crisis. Hypo-metabolism in the white matter of elderly SLC5A8-deficient mice was found using 99mTc-hexamethylpropyleneamine oxime (HMPAO) single-photon emission CT (SPECT). Since the SLC5A8 protein could not be detected in the mouse brain, it was hypothesized that the leukoencephalopathy of aging SLC5A8-deficient mice was caused by the absence of slc5a8 expression in a peripheral organ, i.e. the kidney, where SLC5A8 is strongly expressed. A hyper-excretion of the ketone β-hydroxybutyrate (BHB) in the urine of SLC5A8-deficient mice was observed and showed that SLC5A8-deficient mice suffered a cerebral BHB insufficiency. Elderly SLC5A8-deficient mice also presented altered glucose metabolism. We propose that the continuous renal loss of BHB leads to a chronic energetic deficiency in the brain of elderly SLC5A8-deficient mice who are unable to counterbalance their glucose deficit. This study highlights the importance of alternative energetic substrates in neuroenergetics especially under conditions of restricted glucose availability.

scholarly journals Cognitive impairment in patients with migraine: causes, principles of effective prevention and treatment

2018 ◽  
Vol 10 (3) ◽  
pp. 141-149
Author(s):  
V. A. Golovacheva ◽  
K. A. Pozhidaev ◽  
A. A. Golovacheva
Keyword(s):  
Clinical Trials ◽  
Cognitive Impairment ◽  
Anxiety Disorder ◽  
White Matter ◽  
Effective Prevention ◽  
Pathogenetic Role ◽  
Brain White Matter ◽  
Prevention And Treatment ◽  
The Brain

Cognitive impairment (CI) is common in patients with migraine; its causes and pathogenesis continue to be discussed. Some authors consider that migraine proper does not lead to decreased cognitive functions, neuroimaging changes in the brain white matter are asymptomatic in migraine; and CI in patients with this condition is caused by comorbidities (depression, anxiety disorder) and/or concurrent cerebrovascular and neurodegenerative diseases. Other authors report the pathogenetic role of migraine in the development of CI and the importance of the frequency of headache attacks and neuroimaging changes in the brain matter in migraine. The paper reviews clinical trials dealing with the prevalence, causes, and pathogenesis of CI in patients with migraine. It sets forth the current principles of prevention and treatment of CI in patients with this condition.

scholarly journals A higher proportion of ermin-immunopositive oligodendrocytes in areas of remyelination

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256155
Author(s):  
Intakhar Ahmad ◽  
Stig Wergeland ◽  
Eystein Oveland ◽  
Lars Bø
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Corpus Callosum ◽  
Mouse Model ◽  
Grey Matter ◽  
Early Stage ◽  
Relative Proportion ◽  
Normal Appearing White Matter ◽  
The Brain

Incomplete remyelination is frequent in multiple sclerosis (MS)-lesions, but there is no established marker for recent remyelination. We investigated the role of the oligodendrocyte/myelin protein ermin in de- and remyelination in the cuprizone (CPZ) mouse model, and in MS. The density of ermin+ oligodendrocytes in the brain was significantly decreased after one week of CPZ exposure (p < 0.02). The relative proportion of ermin+ cells compared to cells positive for the late-stage oligodendrocyte marker Nogo-A increased at the onset of remyelination in the corpus callosum (p < 0.02). The density of ermin-positive cells increased in the corpus callosum during the CPZ-phase of extensive remyelination (p < 0.0001). In MS, the density of ermin+ cells was higher in remyelinated lesion areas compared to non-remyelinated areas both in white- (p < 0.0001) and grey matter (p < 0.0001) and compared to normal-appearing white matter (p < 0.001). Ermin immunopositive cells in MS-lesions were not immunopositive for the early-stage oligodendrocyte markers O4 and O1, but a subpopulation was immunopositive for Nogo-A. The data suggest a relatively higher proportion of ermin immunopositivity in oligodendrocytes compared to Nogo-A indicates recent or ongoing remyelination.

On the microstructural origin of brain white matter hydraulic permeability

2021 ◽  
Vol 118 (36) ◽  
pp. e2105328118
Author(s):  
Marco Vidotto ◽  
Andrea Bernardini ◽  
Marco Trovatelli ◽  
Elena De Momi ◽  
Daniele Dini
Keyword(s):  
White Matter ◽  
Corpus Callosum ◽  
Drug Transport ◽  
Three Dimensional ◽  
Principal Component ◽  
Hydraulic Permeability ◽  
Convection Enhanced Delivery ◽  
Brain White Matter ◽  
Significant Difference ◽  
The Brain

Brain microstructure plays a key role in driving the transport of drug molecules directly administered to the brain tissue, as in Convection-Enhanced Delivery procedures. The proposed research analyzes the hydraulic permeability of two white matter (WM) areas (corpus callosum and fornix) whose three-dimensional microstructure was reconstructed starting from the acquisition of electron microscopy images. We cut the two volumes with 20 equally spaced planes distributed along two perpendicular directions, and, on each plane, we computed the corresponding permeability vector. Then, we considered that the WM structure is mainly composed of elongated and parallel axons, and, using a principal component analysis, we defined two principal directions, parallel and perpendicular, with respect to the axons’ main direction. The latter were used to define a reference frame onto which the permeability vectors were projected to finally obtain the permeability along the parallel and perpendicular directions. The results show a statistically significant difference between parallel and perpendicular permeability, with a ratio of about two in both the WM structures analyzed, thus demonstrating their anisotropic behavior. Moreover, we find a significant difference between permeability in corpus callosum and fornix, which suggests that the WM heterogeneity should also be considered when modeling drug transport in the brain. Our findings, which demonstrate and quantify the anisotropic and heterogeneous character of the WM, represent a fundamental contribution not only for drug-delivery modeling, but also for shedding light on the interstitial transport mechanisms in the extracellular space.

6. What do more intelligent brains look like?

2020 ◽  
pp. 83-90
Author(s):  
Ian J. Deary
Keyword(s):  
White Matter ◽  
General Intelligence ◽  
Total Brain Volume ◽  
Brain White Matter ◽  
Total Brain ◽  
Lothian Birth Cohort ◽  
Intelligence Test Scores ◽  
Intelligence Scores ◽  
The Brain ◽  
Brain Connections

‘What do more intelligent brains look like?’ considers a study that used data from the Lothian Birth Cohort 1936 to test the strength of the correlation between the general intelligence scores of the participants and different measures of their brain’s structure. Magnetic resonance imaging was used to measure total brain volume, brain cortical thickness, brain white matter integrity (or health), and brain white matter hyperintensities. The study showed that people who have higher general intelligence tend to have larger brains, thicker grey matter on the surface of the brain, and healthier white matter brain connections. The associations are not strong, but some aspects of brain structure do relate to intelligence test scores.

scholarly journals Large-Scale Evidence for an Association Between Peripheral Inflammation and White Matter Free Water in Schizophrenia and Healthy Individuals

2020 ◽  
Author(s):  
Maria A Di Biase ◽  
Andrew Zalesky ◽  
Suheyla Cetin-Karayumak ◽  
Yogesh Rathi ◽  
Jinglei Lv ◽  
...  
Keyword(s):  
White Matter ◽  
Large Scale ◽  
Interleukin 2 ◽  
Free Water ◽  
Markers Of Inflammation ◽  
Brain White Matter ◽  
Inflammatory Processes ◽  
Weighted Magnetic Resonance Imaging

Abstract Introduction Clarifying the role of neuroinflammation in schizophrenia is subject to its detection in the living brain. Free-water (FW) imaging is an in vivo diffusion-weighted magnetic resonance imaging (dMRI) technique that measures water molecules freely diffusing in the brain and is hypothesized to detect inflammatory processes. Here, we aimed to establish a link between peripheral markers of inflammation and FW in brain white matter. Methods All data were obtained from the Australian Schizophrenia Research Bank (ASRB) across 5 Australian states and territories. We first tested for the presence of peripheral cytokine deregulation in schizophrenia, using a large sample (N = 1143) comprising the ASRB. We next determined the extent to which individual variation in 8 circulating pro-/anti-inflammatory cytokines related to FW in brain white matter, imaged in a subset (n = 308) of patients and controls. Results Patients with schizophrenia showed reduced interleukin-2 (IL-2) (t = −3.56, P = .0004) and IL-12(p70) (t = −2.84, P = .005) and increased IL-6 (t = 3.56, P = .0004), IL-8 (t = 3.8, P = .0002), and TNFα (t = 4.30, P &lt; .0001). Higher proinflammatory signaling of IL-6 (t = 3.4, P = .0007) and TNFα (t = 2.7, P = .0007) was associated with higher FW levels in white matter. The reciprocal increases in serum cytokines and FW were spatially widespread in patients encompassing most major fibers; conversely, in controls, the relationship was confined to the anterior corpus callosum and thalamic radiations. No relationships were observed with alternative dMRI measures, including the fractional anisotropy and tissue-related FA. Conclusions We report widespread deregulation of cytokines in schizophrenia and identify inflammation as a putative mechanism underlying increases in brain FW levels.

Microstructural Hyperelastic Characterization of Brain White Matter in Tension

2019 ◽  
Author(s):  
Mohammadreza Ramzanpour ◽  
Mohammad Hosseini-Farid ◽  
Mariusz Ziejewski ◽  
Ghodrat Karami
Keyword(s):  
Finite Element ◽  
White Matter ◽  
Human Brain ◽  
Volume Fraction ◽  
Fibrous Composite ◽  
Diffuse Axonal Injury ◽  
Stiffness Ratio ◽  
Fibrous Composite Material ◽  
Brain White Matter ◽  
The Brain

Abstract Axons as microstructural constituent elements of brain white matter are highly oriented in extracellular matrix (ECM) in one direction. Therefore, it is possible to model the human brain white matter as a unidirectional fibrous composite material. A micromechanical finite element model of the brain white matter is developed to indirectly measure the brain white matter constituents’ properties including axon and ECM under tensile loading. Experimental tension test on corona radiata conducted by Budday et al. 2017 [1] is used in this study and one-term Ogden hyperelastic constitutive model is applied to characterize its behavior. By the application of genetic algorithm (GA) as a black box optimization method, the Ogden hyperelastic parameters of axon and ECM minimizing the error between numerical finite element simulation and experimental results are measured. Inverse analysis is conducted on the resultant optimized parameters shows high correlation of coefficient (&gt;99%) between the numerical and experimental data which verifies the accuracy of the optimization procedure. The volume fraction of axons in porcine brain white matter is taken to be 52.7% and the stiffness ratio of axon to ECM is perceived to be 3.0. As these values are not accurately known for human brain white matter, we study the material properties of axon and ECM for different stiffness ratio and axon volume fraction values. The results of this study helps to better understand the micromechanical structure of the brain and micro-level injuries such as diffuse axonal injury.

Fractional anisotropy and mean diffusivity parameters of the brain white matter tracts in preterm infants: reproducibility of region-of-interest measurements

2011 ◽  
Vol 42 (2) ◽  
pp. 175-182 ◽  
Author(s):  
Virva K. Lepomäki ◽  
◽  
Teemu P. Paavilainen ◽  
Saija A. M. Hurme ◽  
Markku E. Komu ◽  
...  
Keyword(s):  
White Matter ◽  
Fractional Anisotropy ◽  
Preterm Infants ◽  
Mean Diffusivity ◽  
Region Of Interest ◽  
White Matter Tracts ◽  
Brain White Matter ◽  
The Brain

scholarly journals Identification of Novel Roles of the Cytochrome P450 System in Early Embryogenesis: Effects on Vasculogenesis and Retinoic Acid Homeostasis

2003 ◽  
Vol 23 (17) ◽  
pp. 6103-6116 ◽  
Author(s):  
Diana M. E. Otto ◽  
Colin J. Henderson ◽  
Dianne Carrie ◽  
Megan Davey ◽  
Thomas E. Gundersen ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Retinoic Acid ◽  
Cell Types ◽  
Monooxygenase System ◽  
Cytochrome P450 System ◽  
Expression Of Genes ◽  
Close Relationship ◽  
Metabolism Of Xenobiotics ◽  
The Brain

ABSTRACT The cytochrome P450-dependent monooxygenase system catalyzes the metabolism of xenobiotics and endogenous compounds, including hormones and retinoic acid. In order to establish the role of these enzymes in embryogenesis, we have inactivated the system through the deletion of the gene for the electron donor to all microsomal P450 proteins, cytochrome P450 reductase (Cpr). Mouse embryos homozygous for this deletion died in early to middle gestation (∼9.5 days postcoitum [dpc]) and exhibited a number of novel phenotypes, including the severe inhibition of vasculogenesis and hematopoiesis. In addition, defects in the brain, limbs, and cell types where CPR was shown to be expressed were observed. Some of the observed abnormalities have been associated with perturbations in retinoic acid homeostasis in later embryogenesis. Consistent with this possibility, embryos at 9.5 dpc had significantly elevated levels of retinoic acid and reduced levels of retinol. Further, some of the observed phenotypes could be either reversed or exacerbated by decreasing or increasing maternal retinoic acid exposure, respectively. Detailed analysis demonstrated a close relationship between the observed phenotype and the expression of genes controlling vasculogenesis. These data demonstrate that the cytochrome P450 system plays a key role in early embryonic development; this process appears to be, at least in part, controlled by regional concentrations of retinoic acid and has profound effects on blood vessel formation.

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