Roles of the prostaglandin E2 receptors EP subtypes in Alzheimer’s disease

Wei, Lili; Shen, Yongjia; Zhang, Yingchun; Hu, Xingyue; Lu, Peiling; Wang, Li; Chen, Wei

doi:10.1007/s12264-010-0703-z

Cited by 12 publications

(7 citation statements)

References 45 publications

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“…The most direct indication of the complexity of MSC immune-modulatory effects is exemplified by our findings for prostaglandin E2 receptor (PTGER2), a proinflammatory factor, highly elevated in AD patients and implicated in AD progression [52,53]. PTGER2 can be neurotoxic [54], but on the other hand PTGER2 signalling is implicated for its potential role in longterm synaptic plasticity and cognitive function [55]. The observed MSC-related decreased expression of PTGER2 in the cortex while increased in the hippocampus requires further study.…”

Section: Hippocampus -Nacl Msc D28mentioning

confidence: 80%

Effect of systemic transplantation of bone marrow‐derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice

Naaldijk

Jäger

Fabian

et al. 2016

Neuropathology Appl Neurobio

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Aims Mesenchymal stem cells (MSC) have recently attracted interest as a potential basis for a cell‐based therapy of AD. We investigated the putative immune‐modulatory effects in neuroinflammation of systemic transplantation of MSC into APP/PS1 transgenic mice. Methods 106 MSC were injected into APP/PS1 mice via the tail vein and histological analysis was performed for microglia and amyloid (pE3‐Aβ) plaque numbers, glial distribution and pE3‐Aβ plaque size. In addition, a biochemical analysis by qPCR for pro‐inflammatory, chemoattractant and neurotrophic factors was performed. Results MSC are associated with pE3‐Aβ plaques. The effects of transplantation on microglia‐associated pathology could be observed after 28 days. Animals showed a reduction in microglial numbers in the cortex and in microglia size. Gene expression was reduced for TNF‐α, IL‐6, MCP‐1, and for NGF, in MSC recipients. Also, we investigated for the first time and found no changes in expression of IL‐10, CCR5, BDNF, VEGF and IFNγ. PTGER2 expression levels were increased in the hippocampus but were reduced in the cortex of MSC recipients. While there were no transplant‐related changes in pE3‐Aβ plaque numbers, a reduction in the size of pE3‐Aβ plaques was observed in the hippocampus of transplant recipients. Conclusion This is the first study to show reduction in pE3‐Aβ plaque size. pE3‐Aβ plaques have gained attention as potential key participants in AD due to their increased aggregation propensity, the possibility for the initial seeding event, resistance against degradation and neurotoxicity. These findings support the hypothesis that MSC‐transplants may affect AD pathology via an immune‐modulatory function that includes an effect on microglial cells.

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Section: Hippocampus -Nacl Msc D28mentioning

confidence: 80%

Effect of systemic transplantation of bone marrow‐derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice

Naaldijk

Jäger

Fabian

et al. 2016

Neuropathology Appl Neurobio

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“…In particular, the compelling evidence of a connection between neuroinflammation and AD pathology prompted an investigation of additional Gα q -linked receptors that, like the TP receptor, are reported to be expressed on neurons and can be activated by inflammatory eicosanoids. This led to an evaluation of the PGE2 receptors, EP1 and EP3 24 , the LTD4 receptor, CysLT1 25 , and the LTB4 receptor, BLT1 26 . QBI293 cells stably-expressing hAPP were transfected with constructs encoding each of these receptors, and these cells were subsequently exposed to known agonists.…”

Section: Resultsmentioning

confidence: 99%

Inflammatory Eicosanoids Increase Amyloid Precursor Protein Expression via Activation of Multiple Neuronal Receptors

Herbst-Robinson

Liu

James

et al. 2015

Sci Rep

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Senile plaques comprised of Aβ peptides are a hallmark of Alzheimer’s disease (AD) brain, as are activated glia that release inflammatory molecules, including eicosanoids. Previous studies have demonstrated that amyloid precursor protein (APP) and Aβ levels can be increased through activation of thromboxane A2-prostanoid (TP) receptors on neurons. We demonstrate that TP receptor regulation of APP expression depends on Gαq-signaling and conventional protein kinase C isoforms. Importantly, we discovered that Gαq-linked prostaglandin E2 and leukotriene D4 receptors also regulate APP expression. Prostaglandin E2 and thromboxane A2, as well as total APP levels, were found to be elevated in the brains of aged 5XFAD transgenic mice harboring Aβ plaques and activated glia, suggesting that increased APP expression resulted from eicosanoid binding to Gαq-linked neuronal receptors. Notably, inhibition of eicosanoid synthesis significantly lowered brain APP protein levels in aged 5XFAD mice. These results provide new insights into potential AD therapeutic strategies.

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“…PGE2 is synthesized in either the membrane by microsomal prostaglandin E synthase (mPGES) or in the cytosol by cytosolic PGES (cPGES). As the inducible form, much attention has been paid to the value of mPGES as a potential therapeutic target, and the efficacy of a variety of agonist has been investigated in relevant disease models [ 24 ]. Prostaglandin E2 (PGE2) has been described to exert beneficial and detrimental effects in various neurologic disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Up to now, EP3 receptor is considered to exert neuroprotective effects [ 24 ]. EP3 is the only EP receptor that has three transcriptional splice variants, EP3α, EP3β, and EP3γ.…”

Section: Discussionmentioning

confidence: 99%

PGE2-EP3 signaling pathway contributes to protective effects of misoprostol on cerebral injury in APP/PS1 mice

Tian

Luo

et al. 2016

Oncotarget

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Epidemiological studies indicate chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit the enzymatic activity of the inflammatory cyclooxygenases (COX), reduces the risk of developing Alzheimer's disease (AD) in normal aging populations. Considering multiple adverse side effects of NSAIDs, findings suggest that COX downstream prostaglandin signaling function in the pre-clinical development of AD. Our previous study found that misoprostol, a synthetic prostaglandin E2 (PGE2) receptor agonist, has neuroprotection against brain injury induced by chronic aluminum overload. Here, we investigated the neuroprotective effects and mechanisms of misoprostol on neurodegeneration in overexpressing both amyloid precursor protein (APP) and mutant presenilin 1 (PS1) mice. Here were young group, elderly group, APP/PS1 group and misoprostol-treated group. Mice in misoprostol-treated group were administrated with misoprostol (200 μg·kg−1·d−1, p.o.) five days a week for 20 weeks. The spatial learning and memory function was impaired and karyopycnosis of hippocampal and cortical neurons was observed; amyloid beta (Aβ) deposition was increased; superoxide dismutase (SOD) activity was decreased and malondialdehyde (MDA) content was increased in APP/PS1 mice. However, misoprostol could significantly blunte these changes in APP/PS1 mic. Moreover, the expressions of microsomal PGE2 synthase (mPGES-1), PGE2, PGE2 receptor (EP) 2 and EP4 were increased and EP3 expression was decreased in APP/PS1 mice, while misoprostol reversed these changes. Our present experimental results indicate that misoprostol has a neuroprotective effect on brain injury and neurodegeneration of APP/PS1 mice and that the activation of PGE2-EP3 signaling and inhibition of oxidative stress contribute to the neuroprotective mechanisms of misoprostol.

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Roles of the prostaglandin E2 receptors EP subtypes in Alzheimer’s disease

Cited by 12 publications

References 45 publications

Effect of systemic transplantation of bone marrow‐derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice

Effect of systemic transplantation of bone marrow‐derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice

Inflammatory Eicosanoids Increase Amyloid Precursor Protein Expression via Activation of Multiple Neuronal Receptors

PGE2-EP3 signaling pathway contributes to protective effects of misoprostol on cerebral injury in APP/PS1 mice

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