Gut Microbiota Disorder, Gut Epithelial and Blood–Brain Barrier Dysfunctions in Etiopathogenesis of Dementia: Molecular Mechanisms and Signaling Pathways

ABSTRACTBackgroundCritical functions of the blood-brain barrier (BBB), including cerebral blood flow and vascular response, are regulated by insulin signaling pathways. Therefore, endothelial insulin resistance could lead to vascular dysfunction, which is associated with neurodegenerative diseases such as Alzheimer’s disease (AD).ObjectiveThe objective of the current study is to map the dynamics of insulin-responsive pathways in polarized human cerebral microvascular endothelial cells (hCMEC/D3) cell monolayers, a widely used BBB cell culture model, to identify molecular mechanisms underlying BBB dysfunction in AD.MethodsRNA-Sequencing (RNA-Seq) was performed on hCMEC/D3 cell monolayers with and without insulin treatment at various time points. The Short Time-series Expression Miner (STEM) method was used to identify clusters of genes with distinct and representative patterns. Functional annotation and pathway analysis of the genes from top clusters were conducted using the Webgestalt and Ingenuity Pathway Analysis (IPA) software, respectively.ResultsQuantitative expression differences of 19,971 genes between the insulin-treated and control monolayers at five-time points were determined. STEM software identified 11 clusters with 3061 genes across that displayed various temporal patterns. Gene ontology enrichment analysis performed using the top 5 clusters demonstrated that these genes were enriched in various biological processes associated with AD pathophysiology. The IPA analyses revealed that signaling pathways exacerbating AD pathology such as inflammation were downregulated after insulin treatment (clusters 1 to 3). In contrast, pathways attenuating AD pathology were upregulated, including synaptogenesis and BBB repairment (clusters 4 and 5).ConclusionsThese findings unravel the dynamics of insulin action on the BBB endothelium and inform about downstream signaling cascades that potentially regulate neurovascular unit (NVU) functions that are disrupted in AD.

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Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice

Journal of Translational Medicine ◽

10.1186/s12967-021-02995-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Xiuli Lin ◽

Yingying Liu ◽

Lili Ma ◽

Xiaomeng Ma ◽

Liping Shen ◽

...

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Gut Microbiota ◽

Blood Brain Barrier ◽

Intestinal Barrier ◽

Brain Barrier ◽

Autoimmune Encephalomyelitis ◽

Gm Csf ◽

Blood Brain ◽

Gut Microbiota Dysbiosis ◽

Experimental Autoimmune

Abstract Background Constipation is a common gastrointestinal dysfunction which has a potential impact on people's immune state and their quality of life. Here we investigated the effects of constipation on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Methods Constipation was induced by loperamide in female C57BL/6 mice. The alternations of gut microbiota, permeability of intestinal barrier and blood–brain barrier, and histopathology of colon were assessed after constipation induction. EAE was induced in the constipation mice. Fecal microbiota transplantation (FMT) was performed from constipation mice into microbiota-depleted mice. Clinical scores, histopathology of inflammation and demyelination, Treg/Th17 and Treg17/Teff17 imbalance both in the peripheral lymphatic organs and central nervous system, cytokines include TGF-β, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, IL-22, and IL-23 in serum were assessed in different groups. Results Compared with the vehicle group, the constipation mice showed gut microbiota dysbiosis, colon inflammation and injury, and increased permeability of intestinal barrier and blood–brain barrier. We found that the clinical and pathological scores of the constipation EAE mice were severer than that of the EAE mice. Compared with the EAE mice, the constipation EAE mice showed reduced percentage of Treg and Treg17 cells, increased percentage of Th17 and Teff17 cells, and decreased ratio of Treg/Th17 and Treg17/Teff17 in the spleen, inguinal lymph nodes, brain, and spinal cord. Moreover, the serum levels of TGF-β, IL-10, and IL-21 were decreased while the GM-CSF, IL-17A, IL-17F, IL-22, and IL-23 were increased in the constipation EAE mice. In addition, these pathological processes could be transferred via their gut microbiota. Conclusions Our results verified that constipation induced gut microbiota dysbiosis exacerbated EAE via aggravating Treg/Th17 and Treg17/Teff17 imbalance and cytokines disturbance in C57BL/6 mice.

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Pseudogene ACTBP2 increases blood–brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in Aβ1–42 microenvironment

Cell Death Discovery ◽

10.1038/s41420-021-00531-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Qianshuo Liu ◽

Xiaobai Liu ◽

Defeng Zhao ◽

Xuelei Ruan ◽

Rui Su ◽

...

Keyword(s):

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Rna Binding ◽

Vital Role ◽

Brain Barrier ◽

Blood Brain ◽

Bbb Permeability ◽

Novel Target ◽

And Function

AbstractThe blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.

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Mesenchymal Stem/Stromal Cell Therapy in Blood–Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects

International Journal of Molecular Sciences ◽

10.3390/ijms221810045 ◽

2021 ◽

Vol 22 (18) ◽

pp. 10045

Author(s):

Phuong Thao Do ◽

Chung-Che Wu ◽

Yung-Hsiao Chiang ◽

Chaur-Jong Hu ◽

Kai-Yun Chen

Keyword(s):

Stem Cells ◽

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Time Window ◽

Brain Regions ◽

Brain Barrier ◽

Therapeutic Effects ◽

Pathophysiological Mechanism ◽

Cell Based Therapy ◽

Blood Brain

Ischemic stroke is the leading cause of mortality and long-term disability worldwide. Disruption of the blood–brain barrier (BBB) is a prominent pathophysiological mechanism, responsible for a series of subsequent inflammatory cascades that exacerbate the damage to brain tissue. However, the benefit of recanalization is limited in most patients because of the narrow therapeutic time window. Recently, mesenchymal stem cells (MSCs) have been assessed as excellent candidates for cell-based therapy in cerebral ischemia, including neuroinflammatory alleviation, angiogenesis and neurogenesis promotion through their paracrine actions. In addition, accumulating evidence on how MSC therapy preserves BBB integrity after stroke may open up novel therapeutic targets for treating cerebrovascular diseases. In this review, we focus on the molecular mechanisms of MSC-based therapy in the ischemia-induced prevention of BBB compromise. Currently, therapeutic effects of MSCs for stroke are primarily based on the fundamental pathogenesis of BBB breakdown, such as attenuating leukocyte infiltration, matrix metalloproteinase (MMP) regulation, antioxidant, anti-inflammation, stabilizing morphology and crosstalk between cellular components of the BBB. We also discuss prospective studies to improve the effectiveness of MSC therapy through enhanced migration into defined brain regions of stem cells. Targeted therapy is a promising new direction and is being prioritized for extensive research.

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Endothelium-targeted deletion of the miR-15a/16-1 cluster ameliorates blood-brain barrier dysfunction in ischemic stroke

Science Signaling ◽

10.1126/scisignal.aay5686 ◽

2020 ◽

Vol 13 (626) ◽

pp. eaay5686 ◽

Cited By ~ 4

Author(s):

Feifei Ma ◽

Ping Sun ◽

Xuejing Zhang ◽

Milton H. Hamblin ◽

Ke-Jie Yin

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Neuronal Loss ◽

Glucose Deprivation ◽

Brain Barrier ◽

Protein Abundance ◽

Barrier Dysfunction ◽

Small Noncoding Rnas ◽

Blood Brain

The blood-brain barrier (BBB) maintains a stable brain microenvironment. Breakdown of BBB integrity during cerebral ischemia initiates a devastating cascade of events that eventually leads to neuronal loss. MicroRNAs are small noncoding RNAs that suppress protein expression, and we previously showed that the miR-15a/16-1 cluster is involved in the pathogenesis of ischemic brain injury. Here, we demonstrated that when subjected to experimentally induced stroke, mice with an endothelial cell (EC)–selective deletion of miR-15a/16-1 had smaller brain infarcts, reduced BBB leakage, and decreased infiltration of peripheral immune cells. These mice also showed reduced infiltration of proinflammatory M1-type microglia/macrophage in the peri-infarct area without changes in the number of resolving M2-type cells. Stroke decreases claudin-5 abundance, and we found that EC-selective miR-15a/16-1 deletion enhanced claudin-5 mRNA and protein abundance in ischemic mouse brains. In cultured mouse brain microvascular ECs (mBMECs), the miR-15a/16-1 cluster directly bound to the 3′ untranslated region (3′UTR) of Claudin-5, and lentivirus-mediated ablation of miR-15a/16-1 diminished oxygen-glucose deprivation (OGD)–induced down-regulation of claudin-5 mRNA and protein abundance and endothelial barrier dysfunction. These findings suggest that genetic deletion of endothelial miR-15a/16-1 suppresses BBB pathologies after ischemic stroke. Elucidating the molecular mechanisms of miR-15a/16-1–mediated BBB dysfunction may enable the discovery of new therapies for ischemic stroke.

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Mechanisms of Blood–Brain Barrier Dysfunction in Traumatic Brain Injury

International Journal of Molecular Sciences ◽

10.3390/ijms21093344 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3344 ◽

Cited By ~ 2

Author(s):

Alison Cash ◽

Michelle H. Theus

Keyword(s):

Blood Brain Barrier ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Brain Injuries ◽

The United States ◽

Brain Barrier ◽

Detection Methods ◽

Secondary Injury ◽

Barrier Dysfunction ◽

Blood Brain

Traumatic brain injuries (TBIs) account for the majority of injury-related deaths in the United States with roughly two million TBIs occurring annually. Due to the spectrum of severity and heterogeneity in TBIs, investigation into the secondary injury is necessary in order to formulate an effective treatment. A mechanical consequence of trauma involves dysregulation of the blood–brain barrier (BBB) which contributes to secondary injury and exposure of peripheral components to the brain parenchyma. Recent studies have shed light on the mechanisms of BBB breakdown in TBI including novel intracellular signaling and cell–cell interactions within the BBB niche. The current review provides an overview of the BBB, novel detection methods for disruption, and the cellular and molecular mechanisms implicated in regulating its stability following TBI.

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