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

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.

scholarly journals Microglial TonEBP mediates LPS-induced inflammation and memory loss as transcriptional cofactor for NF-κB and AP-1

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Gyu Won Jeong ◽  
Hwan Hee Lee ◽  
Whaseon Lee-Kwon ◽  
Hyug Moo Kwon
Keyword(s):  
Microglial Activation ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Myeloid Cells ◽  
Memory Loss ◽  
Neuronal Cell ◽  
Microglial Cell Line ◽  
Bv2 Cells ◽  
Pro Inflammatory Cytokines

Abstract Background Microglia are brain-resident myeloid cells involved in the innate immune response and a variety of neurodegenerative diseases. In macrophages, TonEBP is a transcriptional cofactor of NF-κB which stimulates the transcription of pro-inflammatory genes in response to LPS. Here, we examined the role of microglial TonEBP. Methods We used microglial cell line, BV2 cells. TonEBP was knocked down using lentiviral transduction of shRNA. In animals, TonEBP was deleted from myeloid cells using a line of mouse with floxed TonEBP. Cerulenin was used to block the NF-κB cofactor function of TonEBP. Results TonEBP deficiency blocked the LPS-induced expression of pro-inflammatory cytokines and enzymes in association with decreased activity of NF-κB in BV2 cells. We found that there was also a decreased activity of AP-1 and that TonEBP was a transcriptional cofactor of AP-1 as well as NF-κB. Interestingly, we found that myeloid-specific TonEBP deletion blocked the LPS-induced microglia activation and subsequent neuronal cell death and memory loss. Cerulenin disrupted the assembly of the TonEBP/NF-κB/AP-1/p300 complex and suppressed the LPS-induced microglial activation and the neuronal damages in animals. Conclusions TonEBP is a key mediator of microglial activation and neuroinflammation relevant to neuronal damage. Cerulenin is an effective blocker of the TonEBP actions.

scholarly journals Yoda1 Activates Piezo1 in Vitro to Simulate the Upregulation of Piezo1 in the Infected Brain: Piezo1 Participates in the Immune Activation of Microglia.

2021 ◽  
Author(s):  
Heguo Luo ◽  
Hailin Liu ◽  
Wengong Bian ◽  
Bochao Chen ◽  
Dongxia Yang ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Activation ◽  
Environmental Changes ◽  
Microglial Cells ◽  
Bv2 Cells ◽  
Bacterial Lipopolysaccharides ◽  
Multiple Signaling ◽  
Lps Treatment

Abstract Aim: The expression of Piezo1 in reactive glial cells in the peripherally infected patient's brain was upregulated. This study aimed to determine whether Piezo1 is involved in the immune activation of microglial cells induced by bacterial lipopolysaccharides.Materials and methods: BV2 cells were used as a model of brain microglia. In vitro, Yoda1 was used to activate Piezo1 in BV2 cells, and Piezo1 was simulated for LPS-induced Piezo1 activation to evaluate the role of Piezo1 in microglial inflammatory activation.Key findings: In vitro, LPS upregulates the expression of Piezo1 in microglial cells through TLR4. In the absence of LPS, Yoda1 treatment of microglia produced similar immune function changes as LPS treatment. This indicates that Piezo1 plays a role in LPS-induced microglial immune activation. Specifically, Piezo1-mediated Ca2+ signals are involved in the immune activation of microglia. Piezo1-mediated Ca2+ regulates multiple signaling mechanisms downstream of TLR4, including the JNK1, mTOR and NF-κB signaling pathways, which are related to the immune activation of microglia.Significance: Piezo1 is involved in the immune response of microglia to LPS. Changes in Piezo1 activity may play an indispensable role in the immune response of microglia, and mechanical environmental changes may affect neuroinflammatory progression through Piezo1.

scholarly journals Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways

2021 ◽  
Author(s):  
Kristen Ibanez ◽  
Karen McFarland ◽  
Jennifer Phillips ◽  
Mariet Allen ◽  
Christian B Lessard ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Microglial Cells ◽  
Rodent Models ◽  
Rna Seq ◽  
Tau Pathology ◽  
Gene Dose ◽  
Age Dependent ◽  
Glial Function ◽  
Opposing Effects

The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimer's disease (AD), but little is known about ABI3 function. RNAscope showed Abi3 is expressed in microglial and non-microglial cells, though its increased expression appears to be driven in plaque-associated microglia. Here, we evaluated Abi3-/- mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Expression of Abi3 and Gngt2 are tightly correlated, and elevated, in rodent models of AD. RNA-seq of the Abi3-Gngt2-/- mice revealed robust induction of an AD-associated neurodegenerative signature, including upregulation of Trem2, Plcg2 and Tyrobp. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in A? deposition. Additionally, in Abi3-Gngt2-/- mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function in AD. Our studies also demonstrate that manipulation of glial function could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting such pathways in AD.

scholarly journals Degradation of Alzheimer’s Amyloid-β by a Catalytically Inactive Insulin Degrading Enzyme

2020 ◽  
Author(s):  
Bikash R. Sahoo ◽  
Wenguang Liang ◽  
Wei-Jen Tang ◽  
Ayyalusamy Ramamoorthy
Keyword(s):  
High Speed ◽  
Amyloid Β ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Diffusion Nmr ◽  
Zinc Removal ◽  
Aβ Aggregation ◽  
Aβ Degradation

AbstractInsulin-degrading-enzyme (IDE) is a key target to treat type-2 diabetes, and also known to clear Alzheimer’s amyloid-β (Aβ). However, the development of catalytically inactive IDE mutant (E111QIDE) could risk Aβ clearance. Here, we demonstrate Aβ degradation by E111QIDE and the removal of zinc from the toxic Aβ-Zn complex enabling proteolysis by IDE. Fluorescence and NMR results show delays in Aβ aggregation by both wild-type and E111QIDE in their zinc-bound and unbound states. Diffusion NMR and LC-MS revealed the delayed kinetics is due to Aβ degradation. Remarkably, IDEs exhibited no proteolysis against zinc bound Aβ species as evidenced from high-speed AFM, electron microscopy, chromatography and NMR. On the other hand, zinc removal from the Zn-Aβ complex enabled the proteolysis by IDEs. These findings highlight the role of zinc in switching on/off the proteolysis of Aβ and urge the development potent zinc chelators as a strategic alternative therapeutic for AD.Graphical abstract

scholarly journals Determining the role of IL-4 induced neuroinflammation in microglial activity and amyloid-β using BV2 microglial cells and APP/PS1 transgenic mice

2015 ◽  
Vol 12 (1) ◽  
pp. 41 ◽  
Author(s):  
Clare H Latta ◽  
Tiffany L Sudduth ◽  
Erica M Weekman ◽  
Holly M Brothers ◽  
Erin L Abner ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Amyloid Β ◽  
Microglial Cells ◽  
Bv2 Microglial Cells

scholarly journals Role of RPTPβ/ζ in neuroinflammation and microglia-neuron communication

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Rosalía Fernández-Calle ◽  
Milagros Galán-Llario ◽  
Esther Gramage ◽  
Begoña Zapatería ◽  
Marta Vicente-Rodríguez ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
Conditioned Media ◽  
Microglial Cells ◽  
Receptor Protein ◽  
Mrna Levels ◽  
Bv2 Cells ◽  
The Central Nervous System ◽  
Bv2 Microglial Cells ◽  
The Brain

AbstractPleiotrophin (PTN) is a cytokine that is upregulated in different neuroinflammatory disorders. Using mice with transgenic PTN overexpression in the brain (Ptn-Tg), we have found a positive correlation between iNos and Tnfα mRNA and Ptn mRNA levels in the prefrontal cortex (PFC) of LPS-treated mice. PTN is an inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, which is mainly expressed in the central nervous system. We aimed to test if RPTPβ/ζ is involved in the modulation of neuroinflammatory responses using specific inhibitors of RPTPβ/ζ (MY10 and MY33-3). Treatment with MY10 potentiated LPS-induced microglial responses in the mouse PFC. Surprisingly, MY10 caused a decrease in LPS-induced NF-κB p65 expression, suggesting that RPTPβ/ζ may be involved in a novel mechanism of potentiation of microglial activation independent of the NF-κB p65 pathway. MY33-3 and MY10 limited LPS-induced nitrites production and iNos increases in BV2 microglial cells. SH-SY5Y neuronal cells were treated with the conditioned media from MY10/LPS-treated BV2 cells. Conditioned media from non-stimulated and from LPS-stimulated BV2 cells increased the viability of SH-SY5Y cultures. RPTPβ/ζ inhibition in microglial cells disrupted this neurotrophic effect of microglia, suggesting that RPTPβ/ζ plays a role in the neurotrophic phenotype of microglia and in microglia-neuron communication.

scholarly journals Ethanol Induces Microglial Cell Death via the NOX/ROS/PARP/TRPM2 Signalling Pathway

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1253
Author(s):  
Muhammad Syahreel Azhad Sha’fie ◽  
Sharani Rathakrishnan ◽  
Iffa Nadhira Hazanol ◽  
Mohd Haziq Izzazuddin Dali ◽  
Mohd Ezuan Khayat ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Microglial Cell ◽  
Transient Receptor Potential ◽  
Immune Cell ◽  
Critical Role ◽  
Microglial Cells ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channel

Microglial cells are the primary immune cell resident in the brain. Growing evidence indicates that microglial cells play a prominent role in alcohol-induced brain pathologies. However, alcohol-induced effects on microglial cells and the underlying mechanisms are not fully understood, and evidence exists to support generation of oxidative stress due to NADPH oxidases (NOX_-mediated production of reactive oxygen species (ROS). Here, we investigated the role of the oxidative stress-sensitive Ca2+-permeable transient receptor potential melastatin-related 2 (TRPM2) channel in ethanol (EtOH)-induced microglial cell death using BV2 microglial cells. Like H2O2, exposure to EtOH induced concentration-dependent cell death, assessed using a propidium iodide assay. H2O2/EtOH-induced cell death was inhibited by treatment with TRPM2 channel inhibitors and also treatment with poly(ADP-ribose) polymerase (PARP) inhibitors, demonstrating the critical role of PARP and the TRPM2 channel in EtOH-induced cell death. Exposure to EtOH, as expected, led to an increase in ROS production, shown using imaging of 2’,7’-dichlorofluorescein fluorescence. Consistently, EtOH-induced microglial cell death was suppressed by inhibition of NADPH oxidase (NOX) as well as inhibition of protein kinase C. Taken together, our results suggest that exposure to high doses of ethanol can induce microglial cell death via the NOX/ROS/PARP/TRPM2 signaling pathway, providing novel and potentially important insights into alcohol-induced brain pathologies.

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