Expression of prostaglandin E synthase mRNA is induced in beta-amyloid treated rat astrocytes

doi:10.1016/S0304-3940(00)00926-5

Neuroscience Letters

Volume 283, Issue 3, 14 April 2000, Pages 221-223

https://doi.org/10.1016/S0304-3940(00)00926-5 Get rights and content

Abstract

Deposition of beta-amyloid (Aβ) in the brain is considered to be one of the most critical events in the onset of Alzheimer's disease (AD). In order to identify factors involved in the exacerbation of AD, we investigated transcriptionally Aβ-induced genes using a cDNA subtraction technique in rat astrocytes. One gene obtained was rat prostaglandin (PG) E synthase. In this report, we present the deduced sequence for rat PGE synthase for the first time and demonstrate the induction of PGE synthase mRNA by treatment of cells with Aβ. Our results suggest a possibly significant role of this enzyme in the progression of AD.

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Acknowledgements

We thank Dr Yasumasa Marumoto for helpful discussion. We also thank Ms Maiko Miyajima for technical assistance.

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Epidemiological studies have suggested that the long-term use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX) activity moderates the onset or progression of Alzheimer’s disease (AD). Thus it has been suggested that prostaglandin E₂ (PGE₂), a major end-product of COX, may play a pathogenic role in AD, but the involvement of PGE synthase (PGES), a terminal enzyme downstream from COX, has not been fully elucidated. To examine the involvement in AD pathology of microsomal PGES-1 (mPGES-1), a PGES enzyme, we here prepared primary cerebral neuronal cells from the cerebri of wild-type and mPGES-1-deficient mice and then treated them with β-amyloid (Aβ) fragment 31–35 (Aβ_31–35), which represents the shortest sequence of native Aβ peptide required for neurotoxicity. Treatment of wild-type neuronal cells with Aβ_31–35 induced mPGES-1 gene expression and PGE₂ production, followed by significant apoptotic cell death, but apoptosis was not induced in mPGES-1-deficient cells. Furthermore, the combined treatment of Aβ_31–35 and PGE₂ induced apoptosis in mPGES-1-deficient neuronal cells. These results indicated that mPGES-1 is induced during Aβ-mediated neuronal cell death and is involved in Aβ-induced neurotoxicity associated with AD pathology.
Mitsugumin 29 is transcriptionally induced in senile plaque-associated astrocytes
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After the trypsin treatment, the secondary culture was grown in DMEM containing 10% FCS. Aβ (amino acid 1–40, Anaspec, Fremont, CA, USA) was aggregated as previously described (Satoh et al., 2000). After the astrocytes (first passage cells) reached about 80% confluency, the cells were washed twice with phosphate-buffered saline (PBS), and the medium was replaced with DMEM containing B27 (Life Technologies) supplement.
Astrocytes associated with beta-amyloid (Aβ)-deposited senile plaques are a common neuropathological feature of Alzheimer's disease (AD). There is little doubt that the association of Aβ with the major component in the central nervous system cells significantly influences disease progression, however, the molecular mechanisms by which Aβ contributes to the astrocyte-mediated neuropathological changes have not been well established. In an effort to identify astrocyte-derived molecules that may be closely associated with exacerbation of AD, we identified a novel Aβ-induced rat gene, whose mouse counterpart, mitsugumin 29 (MG29), is known to be involved in intracellular Ca²⁺ homeostasis in skeletal muscle. To evaluate the roles of human MG29 in AD, we investigated its expression in AD brain. In non-AD brains, MG29 mRNA has been detected in neurons, but not in quiescent astrocytes. On the contrary, in AD brains, MG29 is expressed in activated astrocytes associated with senile plaques, but not expressed in neurons around lesions. Human MG29-transfected cells express the protein in the endoplasmic reticulum and the level of expression is involved in Ca²⁺-dependent exocytosis mechanisms. Increased MG29 expression in senile plaques-associated activated astrocytes suggests that intracellular Ca²⁺ turnovers may be changed in these astrocytes. This might be related in sustained Ca²⁺-dependent exocytosis of various transmitters including glutamate, leading to the acceleration of neurodegeneration in the lesion observed in AD.
Induction of COX-2 enzyme and down-regulation of COX-1 expression by lipopolysaccharide (LPS) control prostaglandin E <inf>2</inf> production in astrocytes
2012, Journal of Biological Chemistry
Pathological conditions and pro-inflammatory stimuli in the brain induce cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism mediating the production of prostanoids that, among other actions, have strong vasoactive properties. Although low basal cerebral COX-2 expression has been reported, COX-2 is strongly induced by pro-inflammatory challenges, whereas COX-1 is constitutively expressed. However, the contribution of these enzymes in prostanoid formation varies depending on the stimuli and cell type. Astrocyte feet surround cerebral microvessels and release molecules that can trigger vascular responses. Here, we investigate the regulation of COX-2 induction and its role in prostanoid generation after a pro-inflammatory challenge with the bacterial lipopolysaccharide (LPS) in astroglia. Intracerebral administration of LPS in rodents induced strong COX-2 expression mainly in astroglia and microglia, whereas COX-1 expression was predominant in microglia and did not increase. In cultured astrocytes, LPS strongly induced COX-2 and microsomal prostaglandin-E₂ (PGE₂) synthase-1, mediated by the MyD88-dependent NFκB pathway and influenced by mitogen-activated protein kinase pathways. Studies in COX-deficient cells and using COX inhibitors demonstrated that COX-2 mediated the high production of PGE₂ and, to a lesser extent, other prostanoids after LPS. In contrast, LPS down-regulated COX-1 in an MyD88-dependent fashion, and COX-1 deficiency increased PGE₂ production after LPS. The results show that astrocytes respond to LPS by a COX-2-dependent production of prostanoids, mainly vasoactive PGE₂, and suggest that the coordinated down-regulation of COX-1 facilitates PGE₂ production after TLR-4 activation. These effects might induce cerebral blood flow responses to brain inflammation.
Activated astroglia during chronic inflammation in Alzheimer's disease-Do they neglect their neurosupportive roles?
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Alzheimer's disease (AD) is a neurodegenerative disorder, characterized histopathologically by the extracellular deposition of β-amyloid peptide in senile plaques, as well as intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau protein, extensive neuronal loss and synaptic changes in the hippocampus and cerebral cortex. In addition, the AD brain shows chronic inflammation characterized by an abundance of reactive astrocytes and activated microglia. In the healthy brain, astrocytes provide essential services for brain homeostasis and neuronal function, including metabolic support for neurons in the form of lactate, glutamate uptake and conversion into glutamine, and synthesis of glutathione and its precursors. In AD, a large body of evidence now suggests that by transforming from a basal to a reactive state, astrocytes neglect their neurosupportive functions, thus rendering neurons vulnerable to neurotoxins including pro-inflammatory cytokines and reactive oxygen species. This review will explain the normal functions of astrocytes, and how these cells might be activated to turn into inflammatory cells, actively contributing to neurodegeneration and neglecting their neurosupportive roles (“neuro-neglect hypothesis”). Furthermore, it is proposed that astrocytes might be promising target of therapeutic intervention for Alzheimer's disease, if these compromised functions can be normalized with pharmacological agents that are specifically designed to return astrocytes to a quiescent phenotype or supplement factors which activated astrocytes lack to produce.
Prostaglandin E synthases: Understanding their pathophysiological roles through mouse genetic models
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Citation Excerpt :
Induction of mPGES-1 was observed in various areas and various kinds of cells in the brain. Treatment of rat astrocytes with β-amyloid also induced mPGES-1 expression [39]. In clinical views, treatment with COX inhibitors slowed progression of Alzheimer's disease, and both COX-2 expression and PGE2 levels were elevated in brains from Alzheimer's disease patients [40,41].
Prostaglandin E synthase (PGES), which converts cyclooxygenase (COX)-derived prostaglandin H₂ (PGH₂) to PGE₂, is known to comprise a group of at least three structurally and biologically distinct enzymes. Two of them are membrane-bound and have been designated as mPGES-1 and mPGES-2. mPGES-1 is a perinuclear protein that is markedly induced by proinflammatory stimuli and downregulated by anti-inflammatory glucocorticoids as in the case of COX-2. It is functionally coupled with COX-2 in marked preference to COX-1. mPGES-2 is synthesized as a Golgi membrane-associated protein, and the proteolytic removal of the N-terminal hydrophobic domain leads to the formation of a mature cytosolic enzyme. This enzyme is rather constitutively expressed in various cells and tissues and is functionally coupled with both COX-1 and COX-2. Cytosolic PGES (cPGES) is constitutively expressed in a wide variety of cells and is functionally linked to COX-1 to promote immediate PGE₂ production. Recently, mice have been engineered with specific deletions in each of these three PGES enzymes. In this review, we summarize the current understanding of the in vivo roles of PGES enzymes by knockout mouse studies and provide an overview of their biochemical properties.
Prostaglandin E<inf>2</inf> synthases in neurologic homeostasis and disease
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Prostaglandin E₂ synthases (PGES) currently comprise a group of three structurally and biologically distinct molecules. These enzymes are part of an important and complex paracrine signaling system involved in a wide range of biological processes. This review focuses on the normal physiological and pathological roles of these enzymes in the nervous system. Specific topics include the role of PGES(s) in fever and sickness behavior, inflammatory pain, and neural disease. Although the field is in its early stages, ongoing development of selective PGES inhibitors for possible use in people creates a significant need for more fully understanding the biological roles of these important enzymes.

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Expression of prostaglandin E synthase mRNA is induced in beta-amyloid treated rat astrocytes

Abstract

Section snippets

Acknowledgements

Neurobiol. Aging

Neuroscience

Eur. J. Pharmacol.

Brain Res.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Brain Res. Rev.

J. Biol. Chem.

Neuroscience

Exp. Neurol.

Do non-steroidal anti-inflammatory drugs decrease the risk for Alzheimer's disease?

The Rotteerdam study, Neurology