Inflammatory prostaglandin E₂ signaling in a mouse model of Alzheimer disease

Abstract

Objective There is significant evidence for a central role of inflammation in the development of Alzheimer’s disease (AD). Epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD in healthy aging populations. As NSAIDs inhibit the enzymatic activity of the inflammatory cyclooxygenases COX-1 and COX-2, these findings suggest that downstream prostaglandin signaling pathways function in the pre-clinical development of AD. Here, we investigate the function of prostaglandin E2 (PGE2) signaling through its EP3 receptor in the neuroinflammatory response to Aβ peptide. Methods The function of PGE2 signaling through its EP3 receptor was examined in vivo a model of subacute neuroinflammation induced by administration of Aβ42 peptides. Our findings were then confirmed in young adult APPSwe-PS1 ΔE9 transgenic mice. Results Deletion of the PGE2 EP3 receptor in a model of Aβ42 peptide-induced neuroinflammation reduced pro-inflammatory gene expression, cytokine production, and oxidative stress. In the APPSwe-PS1 ΔE9 model of Familial AD, deletion of the EP3 receptor blocked induction of pro-inflammatory gene and protein expression and lipid peroxidation. In addition, levels of Aβ peptides were significantly decreased, as were BACE-1 and β-CTF levels, suggesting that generation of Aβ peptides may be increased as a result of pro-inflammatory EP3 signaling. Finally, deletion of EP3 receptor significantly reversed the decline in pre-synaptic proteins seen in APPSwe-PS1 ΔE9 mice. Interpretation Our findings identify the PGE2 EP3 receptor as a novel pro-inflammatory, pro-amyloidogenic, and synaptotoxic signaling pathway, and suggest a role for COX-PGE2-EP3 signaling in the development of AD.

Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

“…We then assessed effects of microglial Ep2 deletion on synaptic integrity by quantifying levels of candidate synaptic proteins ( Figure 7, B and C). The loss of synaptophysin correlates with progression of cognitive decline in AD development (46); moreover, studies in transgenic mouse AD models have demonstrated that presynaptic proteins are disrupted early during amyloid accumulation (21,47), with loss of postsynaptic markers occurring at more advanced stages of pathology (48). At 8-9 months, we found a decrease in levels of the presynaptic proteins synaptophysin and ed whether microglial Ep2 negatively affects memory function in the setting of Aβ 42 -mediated inflammation.…”

“…In addition, early-stage AD is characterized by increased cerebrospinal fluid levels of PGE 2 (19,20), supporting the hypothesis that inflammatory actions of brain COX/PGE 2 may underlie preclinical development of AD. Consistently, studies in AD model mice demonstrate reduced amyloid pathology with global deletion of individual PGE 2 G protein-coupled receptors (21)(22)(23), and additional studies have shown a suppressive signaling effect of the PGE 2 receptor EP2 on Aβ 42 phagocytosis (24,25). These studies, along with the recent demonstration of a broad regulatory function of EP2 signaling on cell cycle, cytoskeletal, and immune genes in quiescent microglia (26), suggest that microglial EP2 signaling may be a general suppressor of immune and nonimmune processes that protect against onset and progression of AD pathology.…”

“…Immunostaining of paraformaldehyde-fixed mouse sections was carried out as previously described (21). Antibodies used include anti-rat CD68 (1:1,000 dilution; AbD Serotec), antirabbit IBA1 (1:2,000 dilution; Wako), and anti-mouse 6E10 for human Aβ (1:2,000 dilution; Covance).…”

Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury

“…[4][5][6] PGE 2 receptor EP3 (EP3R) is expressed mainly by neurons and activated glial cells in brain 7,8 and is associated with neuronal death. 8,9 Of the four G-proteincoupled PGE 2 receptors, EP3R is unique in its ability to bind to multiple G-proteins based on different spliced carboxy-terminal tail isoforms. 10 Although it signals primarily via Gi/Gs, EP3R can also be linked to the G 12/13 protein, resulting in activation of the small G-protein Rho.…”

The Role of Inflammatory Mediators in the Pathogenesis of Alzheimer’s Disease

“…85,[95][96][97] In addition, recent findings in mouse models suggest a role for COX/prostaglandin E 2 signalling in the development of AD. 98 …”