ABSTRACT
Transferrin (Tf) is an important iron-binding protein postulated to play a key role in iron ion (Fe) absorption via the Tf receptor (TfR), which potentially contributes to the pathogenesis of Alzheimer's disease (AD). However, the role of Tf in AD remains unknown. Using mouse-derived neurons and APP/PS1 transgenic (Tg) mice as model systems, we firstly revealed the mechanisms of APH-1α/1ß and presenilin 1 (PS1) upregulation by Fe in prostaglandin (PG) E2- and PGD2-dependent mechanisms. Specifically, Fe stimulated the expression of mPGES-1 and the production of PGE2 and PGD2 via the Tf and TfR system. Highly accumulated PGE2 markedly induced the expression of anterior pharynx-defective-1α and -1ß (APH-1α/1ß) and PS1 via an EP receptor-dependent mechanism. In contrast, PGD2 suppressed the expression of APH-1α/1ß and PS1 via a prostaglandin D2 (DP) receptor-dependent mechanism. As the natural dehydrated product of PGD2, 15d-PGJ2 exerts inhibitory effects on the expression of APH-1α/1ß and PS1 in a peroxisome proliferator-activated receptor (PPAR) γ-dependent manner. The expression of APH-1α/1ß and PS1 ultimately determined the production and deposition of ß-amyloid protein (Aß), an effect that potentially contributes to the pathogenesis of AD.
Subject(s)
Dinoprostone/pharmacology , Endopeptidases/metabolism , Iron/pharmacology , Membrane Proteins/metabolism , Presenilin-1/metabolism , Prostaglandin D2/pharmacology , Transferrin/metabolism , Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Brain , Cell Line, Tumor , Dinoprostone/metabolism , Gene Expression Regulation/drug effects , Infusions, Intraventricular , Iron/metabolism , Maze Learning , Mice , Mice, Transgenic , Nitrobenzenes/pharmacology , Presenilin-1/genetics , Prostaglandin D2/metabolism , Receptors, Transferrin/genetics , Receptors, Transferrin/metabolism , Sulfonamides/pharmacologyABSTRACT
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 Aß1-42 oligomers but also Aß1-42 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 ß-amyloid protein (Aß)1-42 in ß-amyloid plaques (APs), which contribute to the cognitive decline of AD.