Fibrillar beta-amyloid peptide Aβ1–40 activates microglial proliferation via stimulating TNF-α release and H2O2 derived from NADPH oxidase: a cell culture study

Jekabsone, Aistė; Mander, Palwinder K.; Tickler, Anna K.; Sharpe, Martyn A.; Brown, Guy C.

doi:10.1186/1742-2094-3-24

Cited by 114 publications

(57 citation statements)

References 37 publications

(48 reference statements)

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“…The NADPH oxidase present in microglia is known as PHOX. PHOX stays inactive in steady state, but becomes activated in the presence of Aβ peptides and generates superoxide free radicals, which are eventually converted to H 2 O 2 [39, 40]. Although H 2 O 2 is not a free radical, it can potentially generate highly reactive hydroxyl (•OH) free radicals by reacting with several reduced metal ions causing extensive neuronal damage [41].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective and Neurorescue Effects of a Novel Polymeric Nanoparticle Formulation of Curcumin (NanoCurc™) in the Neuronal Cell Culture and Animal Model: Implications for Alzheimer's disease

Ray

Bisht

Maitra

et al. 2011

JAD

146

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Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques within the brain parenchyma followed by synaptic loss and neuronal death. Deposited Aβ reacts with activated microglia to produce reactive oxygen species (ROS) and cytochemokines, which lead to severe neuroinflammation. Curcumin is a yellow polyphenol compound found in turmeric, a widely used culinary ingredient that possesses anti-inflammatory and anti-cancer properties and may show efficacy as a potential therapeutic agent in several neuro-inflammatory diseases including AD. However, poor aqueous solubility and sub-optimal systemic absorption from the gastrointestinal tract may represent factors contributing to its failure in clinical trials. To increase curcumin’s bioavailability, a polymeric nanoparticle encapsulated curcumin (NanoCurc™) was formulated which is completely water soluble. NanoCurc™ treatment protects neuronally differentiated human SK-N-SH cells from ROS (H2O2) mediated insults. NanoCurc™ also rescues differentiated human SK-N-SH cells, which were previously insulted with H2O2. In vivo, intraperitoneal (IP) NanoCurc™ injection at a dose of 25 mg/kg twice daily in athymic mice resulted in significant curcumin levels in the brain (0.32 μg/g). Biochemical study of NanoCurc™-treated athymic mice revealed decreased levels of H2O2 as well as caspase 3 and caspase 7 activities in the brain, accompanied by increased glutathione (GSH) concentrations. Increased free to oxidized glutathione (GSH : GSSH) ratio in athymic mice brain versus controls also indicated a favorable redox intracellular environment. Taken together, these results suggest that NanoCurc™ represents an optimized formulation worthy of assessing the therapeutic value of curcumin in AD.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective and Neurorescue Effects of a Novel Polymeric Nanoparticle Formulation of Curcumin (NanoCurc™) in the Neuronal Cell Culture and Animal Model: Implications for Alzheimer's disease

Ray

Bisht

Maitra

et al. 2011

JAD

146

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“…Importantly however, activation of PHOX alone caused no neuronal death [22], but did activate the microglia to proliferate [29] and release TNFα and IL-1β in response to fibrillar β-amyloid [30]. PHOX has been shown by many other laboratories to be a key regulator of inflammatory activation of microglia [5], and thus potentially a target for anti-inflammatory strategies.…”

Section: Phoxmentioning

confidence: 97%

Mechanisms of inflammatory neurodegeneration: iNOS and NADPH oxidase

Brown

2007

Biochemical Society Transactions

268

171

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Inflammation contributes to a wide variety of brain pathologies, apparently via glia killing neurons. A number of mechanisms by which inflammatory-activated microglia and astrocytes kill neurons have been identified in culture. These include iNOS (inducible nitric oxide synthase), which is expressed in glia only during inflammation, and PHOX (phagocytic NADPH oxidase) found in microglia and acutely activated by inflammation. High levels of iNOS expression in glia cause (i) NO (nitric oxide) inhibition of neuronal respiration, resulting in neuronal depolarization and glutamate release, followed by excitotoxicity, and (ii) glutamate release from astrocytes via calcium-dependent vesicular release. Hypoxia strongly synergizes with iNOS expression to induce neuronal death via mechanism (i), because NO inhibits cytochrome oxidase in competition with oxygen. Activation of PHOX (by cytokines, beta-amyloid, prion protein, ATP or arachidonate) causes microglial proliferation and inflammatory activation; thus PHOX is a key regulator of inflammation. Activation of PHOX alone causes no death, but when combined with expressed iNOS results in extensive neuronal death via peroxynitrite production.

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“…In addition, Aβ stimulates the production of reactive oxygen species (ROS) and reactive nitrogen intermediates such as nitric oxide (NO) [120–122]. Oxidative stress caused by these species is a well-recognized contributor to neuronal loss and is observed early in AD, and activation of microglial NADPH oxidase is believed to be the primary source of ROS (reviewed in ref.…”

Section: Hallmarks Of Microglial Dysfunction In Aging and Alzheimementioning

confidence: 99%

Microglial dysfunction in brain aging and Alzheimer's disease

Mosher

Wyss‐Coray

2014

Biochemical Pharmacology

480

402

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Microglia, the immune cells of the central nervous system, have long been a subject of study in the Alzheimer’s disease (AD) field due to their dramatic responses to the pathophysiology of the disease. With several large-scale genetic studies in the past year implicating microglial molecules in AD, the potential significance of these cells has become more prominent than ever before. As a disease that is tightly linked to aging, it is perhaps not entirely surprising that microglia of the AD brain share some phenotypes with aging microglia. Yet the relative impacts of both conditions on microglia are less frequently considered in concert. Furthermore, microglial “activation” and “neuroinflammation” are commonly analyzed in studies of neurodegeneration but are somewhat ill-defined concepts that in fact encompass multiple cellular processes. In this review, we have enumerated six distinct functions of microglia and discuss the specific effects of both aging and AD. By calling attention to the commonalities of these two states, we hope to inspire new approaches for dissecting microglial mechanisms.

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Fibrillar beta-amyloid peptide Aβ1–40 activates microglial proliferation via stimulating TNF-α release and H2O2 derived from NADPH oxidase: a cell culture study

Cited by 114 publications

References 37 publications

Neuroprotective and Neurorescue Effects of a Novel Polymeric Nanoparticle Formulation of Curcumin (NanoCurc™) in the Neuronal Cell Culture and Animal Model: Implications for Alzheimer's disease

Neuroprotective and Neurorescue Effects of a Novel Polymeric Nanoparticle Formulation of Curcumin (NanoCurc™) in the Neuronal Cell Culture and Animal Model: Implications for Alzheimer's disease

Mechanisms of inflammatory neurodegeneration: iNOS and NADPH oxidase

Microglial dysfunction in brain aging and Alzheimer's disease

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