Prostaglandin I2 is responsible for ameliorating prostaglandin E2 stress in stimulating the expression of tumor necrosis factor α in a β-amyloid protein -dependent mechanism

Abstract

Cyclooxygenase-2 (COX-2) has been found to be induced during the early stage of Alzheimer’s disease (AD). Using mouse-derived astrocyte and APP/PS1 transgenic (Tg) mice as model systems, we firstly elucidated the mechanisms underlying COX-2 metabolic production including prostaglandin (PG)E2- and PGI2-mediated tumor necrosis factor α (TNF-α) regulation. Specifically, PGE2 accumulation in astrocyte activated the p38 and JNK/c-Jun signaling pathways via phosphorylation, resulting in TNF-α expression. In contrast, the administration of PGI2 attenuated the effects of PGE2 in stimulating the production of TNF-α by inhibiting the activity of TNF-α promoter and the binding activity of AP1 on the promoter of TNF-α. Moreover, our data also showed that not only Aβ1-42 oligomers but also Aβ1-42 fibrils have the ability to involve in mediating the antagonistic effects of PGE2 and PGI2 on regulating the expression of TNF-α via a p38- and JNK/c-Jun-dependent, AP1-transactivating mechanism. Reciprocally, the production of TNF-α finally accelerated the deposition of β-amyloid protein (Aβ)1-42 in β-amyloid plaques (APs), which contribute to the cognitive decline of AD.

Integrated communications between cyclooxygenase‐2 and Alzheimer's disease

“…The roles of PGI 2 in AD are complicated. PGI 2 treatment suppressed Ab production via inhibition of the p38 and JNK/c-Jun in APP/PS1 Tg mice (63). PGI 2 stimulated tau phosphorylation in Tau P301S Tg mice (64).…”

International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2Receptors (EP1–4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions

“…On the other hand, it was reported that PGI 2 counteracts PGE 2 -induced IFN-g production levels in mouse brain in an Ab-dependent mechanism (Wang et al, 2016b). Interestingly, another group also demonstrated that PGI 2 ameliorated the exacerbating effect of PGE 2 on cognitive disorder in APPS/PS1 mice (Zheng et al, 2017). Overall, the studies investigating the role of IP and EP receptors in AD are mostly restricted to animal models, thus further studies are warranted to examine whether and how PGI 2 and PGE 2 are involved in the development and/or treatment of AD in humans.…”

Astrocytes as a Therapeutic Target in Alzheimer’s Disease–Comprehensive Review and Recent Developments

“…The upregulation of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) contribute to the pathogenesis of AD, particularly through PGE2 and PGI2, by inducing Aβ production and triggering hyperphosphorylation of tau protein [ 148 ]. DP1, a prostaglandin receptor, is overexpressed in astrocytes and microglia in amyloid plaques in both AD patients and Tg2576 mice [ 149 ].…”