TREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ42 in HMC3 cells

AbstractAlzheimer’s disease (AD) is characterized by the accumulation in the brain of extracellular amyloid β (Aβ) plaques as well as intraneuronal inclusions (neurofibrillary tangles) consisting of total tau and phosphorylated tau. Also present are dystrophic neurites, loss of synapses, neuronal death, and gliosis. AD genetic studies have highlighted the importance of inflammation in this disease by identifying several risk associated immune response genes, including TREM2. TREM2 has been strongly implicated in basic microglia function including, phagocytosis, apoptosis, and the inflammatory response to Aβ in mouse brain and primary cells. These studies show that microglia are key players in the response to Aβ and in the accumulation of AD pathology. However, details are still missing about which apoptotic or inflammatory factors rely on TREM2 in their response to Aβ, especially in human cell lines. Given these previous findings our hypothesis is that TREM2 influences the response to Aβ toxicity by enhancing phagocytosis and inhibiting both the BCL-2 family of apoptotic proteins and pro-inflammatory cytokines. Aβ42 treatment of the human microglial cell line, HMC3 cells, was performed and TREM2 was overexpressed or silenced and the phagocytosis, apoptosis and inflammatory response were evaluated. Results indicate that a robust phagocytic response to Aβ after 24 hours requires TREM2 in HMC3 cells. Also, TREM2 inhibits Aβ induced apoptosis by activating the Mcl-1/Bim complex. TREM2 is involved in activation of IP-10, MIP-1a, and IL-8, while it inhibits FGF-2, VEGF and GRO. Taken together, TREM2 plays a role in enhancing the microglial functional response to Aβ toxicity in HMC3 cells. This novel information suggests that therapeutic strategies that seek to activate TREM2 may not only enhance phagocytosis, but it may also inhibit beneficial inflammatory factors, emphasizing the need to define TREM2-related inflammatory activity in not only mouse models of AD, but also in human AD.

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Neuronutraceuticals Modulate Lipopolysaccharide- or Amyloid-β 1-42 Peptide-Induced Transglutaminase 2 Overexpression as a Marker of Neuroinflammation in Mouse Microglial Cells

Applied Sciences ◽

10.3390/app11125718 ◽

2021 ◽

Vol 11 (12) ◽

pp. 5718

Author(s):

Nicola Gaetano Gatta ◽

Andrea Parente ◽

Francesca Guida ◽

Sabatino Maione ◽

Vittorio Gentile

Keyword(s):

Microglial Cell ◽

Amyloid Β ◽

Transglutaminase 2 ◽

Microglial Cells ◽

Tissue Type ◽

Microglial Cell Line ◽

Bv2 Cells ◽

Important Marker

Background: Tissue type 2 transglutaminase (TG2, E.C. 2.3.2,13) is reported to be involved in the phagocytosis of apoptotic cells in mouse microglial BV2 cells and peripheral macrophages. In this study, by using lipopolysaccharide (LPS)- or amyloid-β 1-42 (Aβ 1-42) peptide-stimulated microglial cell line BV2 and mouse primary microglial cells, we examined the effects of different neuronutraceutical compounds, such as curcumin (Cu) and N-Palmitoylethanolamine (PEA), known for their anti-inflammatory activity, on TG2 and several inflammatory or neuroprotective biomarker expressions. Methods: Mouse BV2 cells were treated with LPS or Aβ1-42 in the presence of curcumin or PEA, in order to evaluate the expression of TG2 and other inflammatory or neuroprotective markers using Real Time-PCR and Western blot analyses. Results: Curcumin and PEA were capable of reducing TG2 expression in mouse microglial cells during co-treatment with LPS or Aβ 1-42. Conclusions: The results show the role of TG2 as an important marker of neuroinflammation and suggest a possible use of curcumin and PEA in order to reduce LPS- or Aβ1-42-induced TG2 overexpression in mouse microglial cells.

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Angiotensin IV suppresses inflammation in the brains of rats with chronic cerebral hypoperfusion

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320318799587 ◽

2018 ◽

Vol 19 (3) ◽

pp. 147032031879958 ◽

Cited By ~ 2

Author(s):

Qing-Guang Wang ◽

Xiao Xue ◽

Yang Yang ◽

Peng-Yu Gong ◽

Teng Jiang ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Neurological Diseases ◽

Amyloid Β ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Angiotensin Iv ◽

Artificial Cerebrospinal Fluid ◽

Ang Iv ◽

The Brain ◽

Pro Inflammatory Cytokines

Introduction: This study aimed to evaluate the influence of central angiotensin IV (Ang IV) infusion on chronic cerebral hypoperfusion (CCH)-related neuropathological changes including amyloid-β (Aβ), hyperphosphorylated tau (p-tau) and the inflammatory response. Materials and methods: Rats with CCH received central infusion of Ang IV, its receptor AT4R antagonist divalinal-Ang IV or artificial cerebrospinal fluid for six weeks. During this procedure, the systolic blood pressure (SBP) was monitored, and the levels of Aβ42, p-tau and pro-inflammatory cytokines in the brain were detected. Results: Rats with CCH exhibited higher levels of Aβ42, p-tau and pro-inflammatory cytokines in the brain when compared with controls. Infusion of Ang IV significantly reduced the expression of pro-inflammatory cytokines in the brains of rats with CCH. Meanwhile, the reduction of pro-inflammatory cytokines levels caused by Ang IV was reversed by divalinal-Ang IV. During the treatment, the SBP in rats was not significantly altered. Conclusion: This study demonstrates for the first time that Ang IV dose-dependently suppresses inflammation through AT4R in the brains of rats with CCH, which is independent from SBP. These findings suggest that Ang IV/AT4R may represent a potential therapeutic target for CCH-related neurological diseases.

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Fast maturation of splenic dendritic cells upon TBI is associated with FLT3/FLT3L signaling

10.1101/2021.11.29.470328 ◽

2021 ◽

Author(s):

Jin Zhang ◽

Zhenghui Li ◽

Akila Chandrasekar ◽

Li Shun ◽

Albert C. Ludolph ◽

...

Keyword(s):

Dendritic Cells ◽

Inflammatory Response ◽

Cross Talk ◽

Ethanol Intoxication ◽

Mhc Ii ◽

Significant Burden ◽

Almost All ◽

Substantial Change ◽

The Brain ◽

Pro Inflammatory Cytokines

Systemic inflammatory consequences remain a significant burden after traumatic brain injury (TBI), with almost all organs affected. The spleen is connected with the brain by autonomic innervation and by soluble mediators, and the cross-talk between brain and spleen may be important to establish the systemic inflammatory response to TBI. Ethanol intoxication, the most common comorbidity of TBI, is posited to influence the peripheral inflammatory response either directly or through the brain-spleen cross-talk. Here we show that TBI causes a substantial change in transcription of genes associated with dendritic cells activation in the spleen, in particular a FLT3/FLT3L induction 3h after TBI, which was enhanced by EI. The FLT3L induction was associated with the phosphorylation of FLT3 receptor in CD11c+ dendritic cells, which enhanced the protein synthesis of a subset of mRNAs, as shown by the increase in pS6, peIF2A levels in dendritic cells. This corresponded to the upregulation of proteins associated with maturation process and immunostimulatory properties such MHC-II, LAMP1 and CD68, and of pro-inflammatory cytokines such as TNFα. Notably, EI enhanced the maturation of dendritic cells. However, whereas TBI decreases expression of the adrenergic 2b receptors on dendritic cells, EI increased it, thus augmenting the chances of cross-talk regulation of immune function by the autonomic system. In conclusion, this data indicates that TBI induces a fast maturation of the immunomodulatory functions of dendritic cells which is associated by FLT3/FLT3L signaling and which is enhanced by EI prior to TBI.

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Ultraviolet irradiation-induced apoptosis does not trigger nuclear fragmentation but translocation of chromatin from nucleus into cytoplasm in the microglial cell-line, BV-2

Brain Research ◽

10.1016/j.brainres.2006.08.122 ◽

2006 ◽

Vol 1121 (1) ◽

pp. 12-21 ◽

Cited By ~ 11

Author(s):

Susanna Zierler ◽

Barbara Klein ◽

Tanja Furtner ◽

Nikolaus Bresgen ◽

Ursula Lütz-Meindl ◽

...

Keyword(s):

Cell Line ◽

Ultraviolet Irradiation ◽

Microglial Cell ◽

Nuclear Fragmentation ◽

Microglial Cell Line ◽

Induced Apoptosis

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Sulforaphane Reverses the Amyloid-β Oligomers Induced Depressive-Like Behavior

Journal of Alzheimer s Disease ◽

10.3233/jad-200397 ◽

2020 ◽

Vol 78 (1) ◽

pp. 127-137 ◽

Cited By ~ 1

Author(s):

Wei Wang ◽

Cuibai Wei ◽

Meina Quan ◽

Tingting Li ◽

Jianping Jia

Keyword(s):

Oxidative Stress ◽

Memory Impairment ◽

Molecular Mechanisms ◽

Psychological Symptoms ◽

Amyloid Β ◽

Serotonergic System ◽

Inflammatory Factors ◽

The Relationship ◽

The Brain ◽

And Oxidative Stress

Background: Depression is one of the most common behavioral and psychological symptoms in people with Alzheimer’s disease (AD). To date, however, the molecular mechanisms underlying the clinical association between depression and AD remained elusive. Objective: Here, we study the relationship between memory impairment and depressive-like behavior in AD animal model, and investigate the potential mechanisms. Methods: Male SD rats were administered amyloid-β oligomers (AβOs) by intracerebroventricular injection, and then the depressive-like behavior, neuroinflammation, oxidative stress, and the serotonergic system were measured in the brain. Sulforaphane (SF), a compound with dual capacities of anti-inflammation and anti-oxidative stress, was injected intraperitoneally to evaluate the therapeutic effect. Results: The results showed that AβOs induced both memory impairment and depressive-like behavior in rats, through the mechanisms of inducing neuroinflammation and oxidative stress, and impairing the serotonergic axis. SF could reduce both inflammatory factors and oxidative stress parameters to protect the serotonergic system and alleviate memory impairment and depressive-like behavior in rats. Conclusion: These results provided insights into the biological mechanisms underlying the clinical link between depressive disorder and AD, and offered new drug options for the treatment of depressive symptoms in dementia.

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Microglial cell‐derived interleukin‐6 influences behavior and inflammatory response in the brain following traumatic brain injury

Glia ◽

10.1002/glia.23758 ◽

2019 ◽

Vol 68 (5) ◽

pp. 999-1016 ◽

Cited By ~ 5

Author(s):

Paula Sanchis ◽

Olaya Fernández‐Gayol ◽

Joel Vizueta ◽

Gemma Comes ◽

Carla Canal ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Inflammatory Response ◽

Interleukin 6 ◽

Microglial Cell ◽

The Brain

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Acanthamoeba culbertsoni Elicits Soluble Factors That Exert Anti-Microglial Cell Activity

Infection and Immunity ◽

10.1128/iai.00047-10 ◽

2010 ◽

Vol 78 (9) ◽

pp. 4001-4011 ◽

Cited By ~ 11

Author(s):

Jenica L. Harrison ◽

Gabriela A. Ferreira ◽

Erinn S. Raborn ◽

Audrey D. Lafrenaye ◽

Francine Marciano-Cabral ◽

...

Keyword(s):

Microglial Cell ◽

Cell Activity ◽

Opportunistic Pathogen ◽

Neonatal Rat ◽

Cell Contact ◽

Soluble Factors ◽

Microglial Cell Line ◽

The Central Nervous System ◽

Acanthamoeba Culbertsoni ◽

Induced Apoptosis

ABSTRACT Acanthamoeba culbertsoni is an opportunistic pathogen that causes granulomatous amoebic encephalitis (GAE), a chronic and often fatal disease of the central nervous system (CNS). A hallmark of GAE is the formation of granulomas around the amoebae. These cellular aggregates consist of microglia, macrophages, lymphocytes, and neutrophils, which produce a myriad of proinflammatory soluble factors. In the present study, it is demonstrated that A. culbertsoni secretes serine peptidases that degrade chemokines and cytokines produced by a mouse microglial cell line (BV-2 cells). Furthermore, soluble factors present in cocultures of A. culbertsoni and BV-2 cells, as well as in cocultures of A. culbertsoni and primary neonatal rat cerebral cortex microglia, induced apoptosis of these macrophage-like cells. Collectively, the results indicate that A. culbertsoni can apply a multiplicity of cell contact-independent modes to target macrophage-like cells that exert antiamoeba activities in the CNS.

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Microglial Activation in the Retina of a Triple-Transgenic Alzheimer’s Disease Mouse Model (3xTg-AD)

International Journal of Molecular Sciences ◽

10.3390/ijms21030816 ◽

2020 ◽

Vol 21 (3) ◽

pp. 816 ◽

Cited By ~ 2

Author(s):

Elena Salobrar-García ◽

Ana C. Rodrigues-Neves ◽

Ana I. Ramírez ◽

Rosa de Hoz ◽

José A. Fernández-Albarral ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Microglial Cell ◽

Amyloid Β ◽

Microglia Activation ◽

Microglial Cells ◽

Retinal Surface ◽

First Time ◽

The Brain

Alzheimer’s disease (AD) is the most common type of dementia in the world. The main biomarkers associated with AD are protein amyloid-β (Aβ) plaques and protein tau neurofibrillary tangles, which are responsible for brain neuroinflammation mediated by microglial cells. Increasing evidence has shown that the retina can also be affected in AD, presenting some molecular and cellular changes in the brain, such as microglia activation. However, there are only a few studies assessing such changes in the retinal microglia in animal models of AD. These studies use retinal sections, which have some limitations. In this study, we performed, for the first time in a triple-transgenic AD mouse model (3xTg-AD), a quantitative morphometric analysis of microglia activation (using the anti-Iba-1 antibody) in retinal whole-mounts, allowing visualization of the entire microglial cell, as well as its localization along the extension of the retina in different layers. Compared to age-matched animals, the retina of 3xTg-AD mice presents a higher number of microglial cells and a thicker microglial cell body area. Moreover, the microglia migrate, reorient, and retract their processes, changing their localization from a parallel to a perpendicular position relative to the retinal surface. These findings demonstrate clear microglia remodeling in the retina of 3xTg-AD mice.

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Treatment with Bifidobacteria can suppress Aβ accumulation and neuroinflammation in APP/PS1 mice

PeerJ ◽

10.7717/peerj.10262 ◽

2020 ◽

Vol 8 ◽

pp. e10262

Author(s):

Qiong Wu ◽

Qifa Li ◽

Xuan Zhang ◽

Michael Ntim ◽

Xuefei Wu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Microglial Activation ◽

Amyloid Β ◽

The Elderly ◽

Inflammatory Factors ◽

Complex Disorder ◽

Tnf Α ◽

The Brain ◽

Excessive Accumulation

Background Alzheimer’s disease (AD), being a complex disorder, is affected either by genetic or environmental factors or both. It is observed that there is an excessive accumulation of amyloid β (Aβ) in the extracellular space of the brain. AD is the first neurodegenerative disease in the elderly, and so far there is no effective treatment. In recent years, many studies have reported that Alzheimer’s disease has a relationship with gut microflora, indicating that regulating gut microbiota could offer therapeutic intervention for AD. This study explored the effect Bifidobacteria has in averting AD. Methods WT and APP/PS1 mice were used for the experiments. The mice were randomly assigned to four groups: WT group, WT + Bi group, AD group (APP/PS1 mouse) and AD + Bi group (Bifidobacteria-treated APP/PS1 mouse). Treatment with Bifidobacteria lasted for 6 months and mice were prepared for immunohistochemistry, immunofluorescence, Thioflavin S staining, Western blotting, PCR and Elisa quantitative assay. Results The results show that after 6 months of treatment with Bifidobacteria signiis to be lesficantly reduces Aβ deposition in cortex and hippocampus of AD mice. The level of insoluble Aβ in the hippocampus and cortex of AD+Bi mice was decreased compared with AD mice. Meanwhile, a significant decrease in the level of soluble Aβ in the cortex of AD+Bi mice but not in the hippocampus was observed. The activation of microglia and the release of inflammatory factors were also determined in this study. From the results, Bifidobacteria inhibited microglial activation and reduced IL-1β, TNF-α, IL-4, IL-6 and INF-γ release. Altogether, these results implied that Bifidobacteria can alleviate the pathological changes of AD through various effects.

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