Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex

Ye, Shi Yang; Apple, Joanna E.; Ren, Xiao; Tang, Fu Lei; Yao, Ling; Wang, Yong Gang; Mei, Lin; Zhou, Yuan Guo; Xiong, Wen-Cheng

doi:10.1186/s12974-019-1633-y

Cited by 19 publications

(17 citation statements)

References 44 publications

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“…Besides, microglias are activated to clear damaged cells and tissues after trauma 33 . However, normal tissues can also be damaged while activated microglia played the role of scavenger in acute phase of injury 34 . As mentioned above, overactivated microglia can produce a large number of different types of inflammatory factors, which can cause neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

FTY720 Reduces Endothelial Cell Apoptosis and Remodels Neurovascular Unit after Experimental Traumatic Brain Injury

Cheng

Gao

et al. 2021

Int. J. Med. Sci.

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Traumatic brain injury (TBI) is a major cause of death and disability worldwide. A sequence of pathological processes occurred when there is TBI. Previous studies showed that sphingosine-1-phosphate receptor 1 (S1PR1) played a critical role in inflammatory response in the brain after TBI. Thus, the present study was designed to evaluate the effects of the S1PR1 modulator FTY720 on neurovascular unit (NVU) after experimental TBI in mice. The weight-drop TBI method was used to induce TBI. Western blot (WB) was performed to determine the levels of SIPR1, claudin-5 and occludin at different time points. FTY720 was intraperitoneally administered to mice after TBI was induced. The terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL) assay was used to assess endothelial cell apoptosis. Immunofluorescence and WB were performed to measure the expression of tight junction proteins: claudin-5 and occludin. Evans blue (EB) permeability assay and brain water content were applied to evaluate the blood-brain barrier (BBB) permeability and brain edema. Immunohistochemistry was performed to assess the activation of astrocytes and microglia. The results showed that FTY720 administration reduced endothelial cell apoptosis and improved BBB permeability. FTY720 also attenuated astrocytes and microglia activation. Furthermore, treatment with FTY720 not only improved neurological function, but also increased the survival rate of mice significantly. These findings suggest that FTY720 administration restored the structure of the NVU after experimental TBI by decreasing endothelial cell apoptosis and attenuating the activation of astrocytes. Moreover, FTY720 might reduce inflammation in the brain by reducing the activation of microglia in TBI mice.

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Section: Discussionmentioning

confidence: 99%

FTY720 Reduces Endothelial Cell Apoptosis and Remodels Neurovascular Unit after Experimental Traumatic Brain Injury

Cheng

Gao

et al. 2021

Int. J. Med. Sci.

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“…Osmotic pump infusion was performed on 6–7-month-old APP/PS1 mice as previously described 9 – 13 . Alzet mini-osmotic pumps (model 1004) were set at an infusion rate of 0.11 μL/h and implanted for 28 days.…”

Section: Methodsmentioning

confidence: 99%

“…Immunohistochemical staining was performed as previously described 9 – 13 . For fixation of the brain, mice were first anesthetized with isoflurane, and brains were fixed by transcardial perfusion with 0.9% saline followed by ice-cold 4% paraformaldehyde in 0.1 M PBS (pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

“…Statistical analysis adopted in the present work was modified from previously description 9 – 13 . The researchers who conducted the immunohistochemical and transcript expression analyses were blinded to both the mouse genotypes and treatment conditions.…”

Section: Methodsmentioning

confidence: 99%

“…As AD progresses, neuronal and glial dysfunctions lead to imbalanced Aβ production and clearance, consequently increasing Aβ burden. Such increased Aβ burden further alters the activation states of microglia and astrocytes 7 , 8 , which contribute to the loss of homeostasis in the central nervous system, further promoting AD pathology with chronic inflammation 9 – 13 .…”

Section: Introductionmentioning

confidence: 99%

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Melanocortin receptor activation alleviates amyloid pathology and glial reactivity in an Alzheimer’s disease transgenic mouse model

Lau

Tian

Shen

et al. 2021

Sci Rep

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with no disease-modifying treatment. AD progression is characterized by cognitive decline, neuroinflammation, and accumulation of amyloid-beta (Aβ) and neurofibrillary tangles in the brain, leading to neuronal and glial dysfunctions. Neuropeptides govern diverse pathophysiological processes and represent key players in AD pathogenesis, regulating synaptic plasticity, glial cell functions and amyloid pathology. Activation of the pro-opiomelanocortin (POMC)-derived neuropeptide and its receptor from the melanocortin receptor (MCR) family have previously been shown to rescue the impairment in hippocampus-dependent synaptic plasticity in the APP/PS1 mouse model of AD. However, the functional roles of MCR signaling in AD conditions, particularly in glial functions, are largely unknown. In this study, we investigated the potential benefits of MCR activation in AD. In APP/PS1 transgenic mice, we demonstrate that MCR activation mediated by the central administration of its agonist D-Tyr MTII substantially reduces Aβ accumulation, while alleviating global inflammation and astrocytic activation, particularly in the hippocampus. MCR activation prominently reduces the A1 subtype of reactive astrocytes, which is considered a key source of astrocytic neurotoxicity in AD. Concordantly, MCR activation suppresses microglial activation, while enhancing their association with amyloid plaques. The blunted activation of microglia may contribute to the reduction in the neurotoxic phenotypes of astrocytes. Importantly, transcriptome analysis reveals that MCR activation restores the impaired homeostatic processes and microglial reactivity in the hippocampus in APP/PS1 mice. Collectively, our findings demonstrate the potential of MCR signaling as therapeutic target for AD.

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Microglia–neuron–vascular interactions in ischemia

Lénárt,

Cserép,

Császár

et al. 2023

Glia

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Cerebral ischemia is a devastating condition that results in impaired blood flow in the brain leading to acute brain injury. As the most common form of stroke, occlusion of cerebral arteries leads to a characteristic sequence of pathophysiological changes in the brain tissue. The mechanisms involved, and comorbidities that determine outcome after an ischemic event appear to be highly heterogeneous. On their own, the processes leading to neuronal injury in the absence of sufficient blood supply to meet the metabolic demand of the cells are complex and manifest at different temporal and spatial scales. While the contribution of non‐neuronal cells to stroke pathophysiology is increasingly recognized, recent data show that microglia, the main immune cells of the central nervous system parenchyma, play previously unrecognized roles in basic physiological processes beyond their inflammatory functions, which markedly change during ischemic conditions. In this review, we aim to discuss some of the known microglia–neuron–vascular interactions assumed to contribute to the acute and delayed pathologies after cerebral ischemia. Because the mechanisms of neuronal injury have been extensively discussed in several excellent previous reviews, here we focus on some recently explored pathways that may directly or indirectly shape neuronal injury through microglia‐related actions. These discoveries suggest that modulating gliovascular processes in different forms of stroke and other neurological disorders might have presently unexplored therapeutic potential in combination with neuroprotective and flow restoration strategies.

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Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex

Cited by 19 publications

References 44 publications

FTY720 Reduces Endothelial Cell Apoptosis and Remodels Neurovascular Unit after Experimental Traumatic Brain Injury

FTY720 Reduces Endothelial Cell Apoptosis and Remodels Neurovascular Unit after Experimental Traumatic Brain Injury

Melanocortin receptor activation alleviates amyloid pathology and glial reactivity in an Alzheimer’s disease transgenic mouse model

Microglia–neuron–vascular interactions in ischemia

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