Enlargement of Aβ aggregates through chemokine-dependent microglial clustering

Huang, Wei; Yen, Feng Chang; Shiao, Young‐Ji; Shie, Feng Shiun; Chan, Jin Lieh; Yang, Cheng; Sung, Yen Jen; Huang, Fong Lee; Tsay, Huey Jen

doi:10.1016/j.neures.2009.01.001

Cited by 17 publications

(19 citation statements)

References 33 publications

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“…Both CCL5 and CXCL3 chemokines emulated act as a chemoattractant and play an active role in recruiting leukocytes into inflammatory sites. CCL5 as a prominent chemokine that mediates the chemotaxis of microglia toward beta-amyloid (Aβ) aggregates observed in Alzheimer's disease (Huang et al, 2009), and it is commonly observed in the microcirculatory system of AD-affected brains, upregulated as a response to a cytokine-mediated increase of ROS (Tripathy et al, 2010). The microglial clustering around neuritic plaques contribute the neuroinflammation, and progressive neurodegeneration and CCL5 down-regulation reduce chemotaxis of microglia toward Aβγaggregates (Huang et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Thymoquinone increases the expression of neuroprotective proteins while decreasing the expression of pro-inflammatory cytokines and the gene expression NFκB pathway signaling targets in LPS/IFNγ -activated BV-2 microglia cells

Cobourne-Duval

Taka

Mendonca

et al. 2018

Journal of Neuroimmunology

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Neuroinflammation and microglial activation are pathological markers of a number of central nervous system (CNS) diseases. Chronic activation of microglia induces the release of excessive amounts of reactive oxygen species (ROS) and pro-inflammatory cytokines. Additionally, chronic microglial activation has been implicated in several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Thymoquinone (TQ) has been identified as one of the major active components of the natural product Nigella sativa seed oil. TQ has been shown to exhibit anti-inflammatory, anti-oxidative, and neuroprotective effects. In this study, lipopolysaccharide (LPS) and interferon gamma (IFNγ) activated BV-2 microglial cells were treated with TQ (12.5 μM for 24 h). We performed quantitative proteomic analysis using Orbitrap/Q-Exactive Proteomic LC-MS/ MS (Liquid chromatography-mass spectrometry) to globally assess changes in protein expression between the treatment groups. Furthermore, we evaluated the ability of TQ to suppress the inflammatory response using ELISArray™ for Inflammatory Cytokines. We also assessed TQ's effect on the gene expression of NFκB signaling targets by profiling 84 key genes via real-time reverse transcription (RT2) PCR array. Our results indicated that TQ treatment of LPS/IFNγ-activated microglial cells significantly increased the expression of 4 antioxidant, neuroprotective proteins: glutaredoxin-3 (21 fold; p < 0.001), biliverdin reductase A (15 fold; p < 0.0001), 3-mercaptopyruvate sulfurtransferase (11 fold; p < 0.01), and mitochondrial lon protease (> 8 fold; p < 0.001) compared to the untreated, activated cells. Furthermore, TQ treatment significantly (P < 0.0001) reduced the expression of inflammatory cytokines, IL-2 = 38%, IL-4 = 19%, IL-6 = 83%, IL-10 = 237%, and IL-17a = 29%, in the activated microglia compared to the untreated, activated which expression levels were significantly elevated compared to the control microglia: IL-2 = 127%, IL-4 = 151%, IL-6 = 670%, IL-10 = 133%, IL-17a = 127%. Upon assessing the gene expression of NFκB signaling targets, this study also demonstrated that TQ treatment of activated microglia resulted in > 7 fold down-regulation of several NFκB signaling targets genes, including interleukin 6 (IL6), complement factor B (CFB), chemokine (C–C motif) ligand 3 (CXCL3), chemokine (C–C) motif ligand 5 (CCL5) compared to the untreated, activated microglia. This modulation in gene expression counteracts the > 10-fold upregulation of these same genes observed in the activated microglia compared to the controls. Our results show that TQ treatment of LPS/IFNγ-activated BV-2 microglial cells induce a significant increase in expression of neuroprotective proteins, a significant decrease in expression inflammatory cytokines, and a decrease in the expression of signaling target genes of the NFκB pathway. Our findings are the first to show that TQ treatment increased the expression of these neuroprotective proteins (biliverdin reductase-A, 3-mercaptopyruvate sulfu...

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Section: Discussionmentioning

confidence: 99%

Thymoquinone increases the expression of neuroprotective proteins while decreasing the expression of pro-inflammatory cytokines and the gene expression NFκB pathway signaling targets in LPS/IFNγ -activated BV-2 microglia cells

Cobourne-Duval

Taka

Mendonca

et al. 2018

Journal of Neuroimmunology

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“…Downstream of CD36 are the focal adhesion-associated proteins p130Cas, Pyk2, and paxillin representing novel members of the tyrosine kinase signaling pathway; assembly of this complex is essential for microglial migration (875). Chemokines may be involved in the recruitment of microglia to senile plaques, because neutralizating antibodies against chemokines significantly attenuated A␤-induced microglial clustering and the enlargement of A␤ aggregates (391). A recent study, however, did not find that the presence of microglia in a mouse model of AD has an impact on plaque load (336).…”

Section: ␤-Amyloidmentioning

confidence: 99%

Physiology of Microglia

Kettenmann

Hanisch

Нода

et al. 2011

Physiological Reviews

3,138

2,981

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Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed “resting microglia.” Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the “activated microglial cell.” This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

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“…Huang [95] used time lapse recording to investigate how microglia are involved in the growth of amyloid plaques. Fucus vesiculosis fucoidan at 10 micromolar concentration was able to inhibit the amyloid induced microglical clustering effect that gave rise to plaques.…”

Section: Therapies From Fucoidanmentioning

confidence: 99%

Therapies from Fucoidan; Multifunctional Marine Polymers

Fitton¹

2011

Marine Drugs

326

225

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Published research on fucoidans increased three fold between 2000 and 2010. These algal derived marine carbohydrate polymers present numerous valuable bioactivities. This review discusses the role for fucoidan in the control of acute and chronic inflammation via selectin blockade, enzyme inhibition and inhibiting the complement cascade. The recent data on toxicology and uptake of fucoidan is detailed together with a discussion on the comparative activities of fractions of fucoidan from different sources. Recent in vivo, in vitro and clinical research related to diverse clinical needs is discussed. Targets include osteoarthritis, kidney and liver disease, neglected infectious diseases, hemopoietic stem cell modulation, protection from radiation damage and treatments for snake envenomation. In recent years, the production of well characterized reproducible fucoidan fractions on a commercial scale has become possible making therapies from fucoidan a realizable goal.

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Enlargement of Aβ aggregates through chemokine-dependent microglial clustering

Cited by 17 publications

References 33 publications

Thymoquinone increases the expression of neuroprotective proteins while decreasing the expression of pro-inflammatory cytokines and the gene expression NFκB pathway signaling targets in LPS/IFNγ -activated BV-2 microglia cells

Thymoquinone increases the expression of neuroprotective proteins while decreasing the expression of pro-inflammatory cytokines and the gene expression NFκB pathway signaling targets in LPS/IFNγ -activated BV-2 microglia cells

Physiology of Microglia

Therapies from Fucoidan; Multifunctional Marine Polymers

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