Microglial Depletion with CSF1R Inhibitor During Chronic Phase of Experimental Traumatic Brain Injury Reduces Neurodegeneration and Neurological Deficits

Journal of Neuroscience, Год журнала: 2020, Номер 40(14), С. 2960 - 2974

Опубликована: Фев. 24, 2020

Chronic neuroinflammation with sustained microglial activation occurs following severe traumatic brain injury (TBI) and is believed to contribute subsequent neurodegeneration neurological deficits. Microglia, the primary innate immune cells in brain, are dependent on colony stimulating factor 1 receptor (CSF1R) signaling for their survival. In this preclinical study, we examined effects of delayed depletion chronically activated microglia functional recovery up 3 months postinjury. A CSF1R inhibitor, Plexxikon (PLX) 5622, was administered adult male C57BL/6J mice at month after controlled cortical impact remove microglia, inhibitor withdrawn 1-week later allow repopulation. Following TBI, repopulated displayed a ramified morphology similar that Sham uninjured mice, whereas vehicle-treated TBI showed typical chronic posttraumatic hypertrophic morphology. PLX5622 treatment limited TBI-associated neuropathological changes postinjury; these included smaller lesion, reduced hippocampal neuron cell death, decreased NOX2- NLRP3 inflammasome-associated neuroinflammation. Furthermore, led widespread transcriptome altered gene pathways involved neuroinflammation, oxidative stress, neuroplasticity. Using variety complementary neurobehavioral tests, PLX5622-treated also had improved long-term motor cognitive function through Together, studies demonstrate phase removal neurotoxic using inhibitors markedly reduce associated neurodegeneration, as well related SIGNIFICANCE STATEMENT Traumatic debilitating disorder can seriously patient's quality life. Microglial-mediated induced contributes deficits on-going neurodegenerative processes. Here, investigated effect breaking neuroinflammatory loop 1-month by pharmacological 5622. Overall, show short-term elimination during followed repopulation results improvements function, suppression stress pathways, reduction persistent These clinically relevant support new concepts therapeutic window may be far longer than traditionally if evolving microglial-mediated inhibited or regulated precise manner.

Язык: Английский

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Astrocyte Activation in Neurovascular Damage and Repair Following Ischaemic Stroke

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(8), С. 4280 - 4280

Опубликована: Апрель 20, 2021

Transient or permanent loss of tissue perfusion due to ischaemic stroke can lead damage the neurovasculature, and disrupt brain homeostasis, causing long-term motor cognitive deficits. Despite promising pre-clinical studies, clinically approved neuroprotective therapies are lacking. Most studies have focused on neurons while ignoring important roles other cells neurovascular unit, such as astrocytes pericytes. Astrocytes for development maintenance blood–brain barrier, structural support, control cerebral blood flow secretion factors. Emerging data suggest that astrocyte activation exerts both beneficial detrimental effects following stroke. Activated provide neuroprotection contribute neurorestoration, but also secrete inflammatory modulators, leading aggravation lesion. more resistant than cell types pathology, exert a regulative effect in response ischaemia. These remain incompletely understood, though they represent an appealing target protection In this review, we summarise astrocytic contributions repair stroke, explore mechanisms promote revascularisation which may be targeted developing novel

Язык: Английский

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Pyroptosis in Alzheimer’s disease: cell type-specific activation in microglia, astrocytes and neurons

Acta Neuropathologica, Год журнала: 2022, Номер 145(2), С. 175 - 195

Опубликована: Дек. 9, 2022

Язык: Английский

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Demyelination precedes axonal loss in the transneuronal spread of human neurodegenerative disease

Brain, Год журнала: 2018, Номер 142(2), С. 426 - 442

Опубликована: Дек. 16, 2018

The spread of neurodegeneration through the human brain network is reported as underlying progression neurodegenerative disorders. However, exact mechanisms remain unknown. visual pathway characterized by its unique hierarchical architecture and, therefore, represents an ideal model to study trans-synaptic degeneration, in contrast complexity neural connectivity whole brain. Here we show two specifically selected patient cohorts, including (i) glaucoma patients with symmetrical bilateral hemifield defects respecting horizontal meridian (n = 25, 14 females, 64.8 ± 10.1 years; versus 13 normal controls similar age/sex distributions); and (ii) multiple sclerosis without optic radiation lesions (to avoid potential effects on diffusivity measures) 30, 25 37.9 10.8 20 controls), that there are measurable topographic changes posterior pathways corresponding primary nerve defects. A significant anisotropic increase water diffusion was detected both cohorts radiations, perpendicular (radial) (a measure myelin integrity) extended more posteriorly than those observed parallel (axial) (reflecting axonal integrity). In glaucoma, which not considered a demyelinating disease, radial within radiations validated topographically linked delay evoked latency, functional demyelination. Radial change also associated asymmetrical reduction thickness calcarine cortex glaucoma. addition, 3 years longitudinal observation cohort revealed anterograde anterior part again retinotopically damage caused neuritis. Finally, animal injury, early glial activation demyelination projections, evidenced presence myelin-laden macrophages. This occurred prior appearance amyloid precursor protein accumulation, indicator disrupted fast transport. demonstrated strong topographical along recognized projections showed pathology precedes loss process, suggesting mechanism may be at least partially mediated components cellular level. findings have broad biological therapeutic implications for other

Язык: Английский

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Cortical Connections Position Primate Area 25 as a Keystone for Interoception, Emotion, and Memory

Journal of Neuroscience, Год журнала: 2018, Номер 38(7), С. 1677 - 1698

Опубликована: Янв. 22, 2018

The structural and functional integrity of subgenual cingulate area 25 (A25) is crucial for emotional expression equilibrium. A25 has a key role in affective networks, its disruption been linked to mood disorders, but cortical connections have yet be systematically or fully studied. Using neural tracers rhesus monkeys, we found that was densely connected with other ventromedial posterior orbitofrontal areas associated emotions homeostasis. A moderate pathway frontopolar 10, an complex cognition, which may regulate dampen negative affect. Beyond the frontal lobe, auditory association memory-related medial temporal cortices, interoceptive-related anterior insula. mostly targeted superficial layers areas, where broadly dispersed terminations comingled modulatory inhibitory disinhibitory microsystems, suggesting dominant excitatory effect. architecture suggest consummate feedback system PFC. Conversely, entorhinal cortex, pathways terminated middle-deep amid strong local microenvironment, gating hippocampal output cortices memory storage. graded laminar patterns how layers, functionally distinct classes neurons can recruited dynamically meet task demands. complement memory, emotion, somatic homeostasis provide circuit basis understand vulnerability psychiatric neurologic disorders. SIGNIFICANCE STATEMENT Integrity prefrontal cortex healthy function. Subgenual emotion dense network positioned recruit large fields cortex. In states, internal autonomic function, transient Constant hyperactivity biomarker depression humans trigger extensive activation balance. between 10 critical link persistent affect, explored therapeutic intervention depression.

Язык: Английский

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Designing multifunctionalized selenium nanoparticles to reverse oxidative stress-induced spinal cord injury by attenuating ROS overproduction and mitochondria dysfunction

Journal of Materials Chemistry B, Год журнала: 2019, Номер 7(16), С. 2648 - 2656

Опубликована: Янв. 1, 2019

Herein, novel multifunctionalized selenium nanoparticles have been rationally designed to reverse oxidative stress-induced spinal cord injury by attenuating ROS overproduction and mitochondria dysfunctionviainactivation of p53 MAPK pathways.

Язык: Английский

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Analyzing microglial phenotypes across neuropathologies: a practical guide

Acta Neuropathologica, Год журнала: 2021, Номер 142(6), С. 923 - 936

Опубликована: Окт. 8, 2021

As extremely sensitive immune cells, microglia act as versatile watchdogs of the central nervous system (CNS) that tightly control tissue homeostasis. Therefore, microglial activation is an early and easily detectable hallmark virtually all neuropsychiatric, neuro-oncological, neurodevelopmental, neurodegenerative neuroinflammatory diseases. The recent introduction novel high-throughput technologies several single-cell methodologies well advances in epigenetic analyses helped to identify new expression profiles, enhancer-landscapes local signaling cues defined diverse previously unappreciated states healthy diseased CNS. Here, we give overview on developments field biology provide a practical guide analyze disease-associated phenotypes both murine human CNS, morphological molecular levels. Finally, technical limitations, potential pitfalls data misinterpretations are discussed well.

Язык: Английский

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Mirror trends of plasticity and stability indicators in primate prefrontal cortex

European Journal of Neuroscience, Год журнала: 2017, Номер 46(8), С. 2392 - 2405

Опубликована: Сен. 18, 2017

Abstract Research on plasticity markers in the cerebral cortex has largely focused their timing of expression and role shaping circuits during critical normal periods. By contrast, little attention been spatial dimension plasticity–stability across cortical areas. The rationale for this analysis is based systematic variation structure that parallels functional specialization raises possibility varying levels plasticity. Here, we investigated adult rhesus monkeys related to synaptic or stability prefrontal limbic eulaminate areas vary laminar structure. Our findings revealed are impoverished three stability: intracortical myelin, lectin Wisteria floribunda agglutinin, which labels perineuronal nets, parvalbumin, expressed a class strong inhibitory neurons. were enriched enzyme calcium/calmodulin‐dependent protein kinase II (Ca MKII ), known enhance Eulaminate have more elaborate architecture than showed opposite trend: they had lower plasticity‐related marker Ca . glial fibrillary acidic ( GFAP activated astrocytes, was also higher areas, suggesting cellular stress correlates with rate circuit reshaping. Elevated may endow flexibility necessary learning memory within an affective context, but render them vulnerable abnormal structural changes, as seen neurologic psychiatric diseases.

Язык: Английский

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A Brief History of Microglial Ultrastructure: Distinctive Features, Phenotypes, and Functions Discovered Over the Past 60 Years by Electron Microscopy

Frontiers in Immunology, Год журнала: 2018, Номер 9

Опубликована: Апрель 25, 2018

The first electron microscope was constructed in 1931. Several decades later, techniques were developed to allow the ultrastructural analysis of microglia by transmission microscopy (EM). In 50 years that followed, important roles have been identified, specifically due resolution currently available only with EM. particular, addition electron-dense staining using immunohistochemical EM methods has allowed identification microglial cell bodies, as well processes, which are difficult recognize EM, and uncover their complex interactions neurons synapses. ability neuronal, astrocytic oligodendrocytic compartments neuropil without any is another invaluable advantage over light for studying intimate cell-cell contacts. technique essential defining synapses, thus providing, among other discoveries, insights into synaptic stripping pruning via phagocytosis extraneous Recent technological advances including serial block-face imaging focused ion beam scanning also facilitated automated acquisition large tissue volumes required reconstruct neuronal circuits 3D at nanometer-resolution. These cutting-edge now becoming increasingly will further revolutionize study across stages lifespan, brain regions, contexts health disease. this mini-review, we focus on distinctive features unique function provided

Язык: Английский

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Brain Ultrastructure: Putting the Pieces Together

Frontiers in Cell and Developmental Biology, Год журнала: 2021, Номер 9

Опубликована: Фев. 18, 2021

Unraveling the fine structure of brain is important to provide a better understanding its normal and abnormal functioning. Application high-resolution electron microscopic techniques gives us an unprecedented opportunity discern details parenchyma at nanoscale resolution, although identifying different cell types their unique features in two-dimensional, or three-dimensional images, remains challenge even experts field. This article provides insights into how identify central nervous system, based on nuclear cytoplasmic features, amongst other characteristics. From basic distinction between neurons supporting cells, glia, differences subcellular compartments, organelles interactions, ultrastructural analyses can changes function during aging disease conditions, such as stroke, neurodegeneration, infection trauma. Brain composed dense mixture neuronal glial bodies, together with intertwined processes. Intracellular components that vary become altered disease, relate nucleoplasmic density, heterochromatin pattern, mitochondria, endoplasmic reticulum Golgi complex, lysosomes, neurosecretory vesicles, cytoskeletal elements (actin, intermediate filaments, microtubules). Applying immunolabeling visualize membrane-bound intracellular proteins cells appreciation subtle these across contexts health disease. Together, our observations reveal simple be used specific types, status, functional relationships brain.

Язык: Английский

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