Transferrin is responsible for mediating the effects of iron ions on the regulation of anterior pharynx-defective-1α/β and Presenilin 1 expression via PGE₂ and PGD₂ at the early stage of Alzheimer’s Disease

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/1β 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 -1β (APH-1α/1β) and PS1 via an EP receptor-dependent mechanism. In contrast, PGD₂ suppressed the expression of APH-1α/1β 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/1β and PS1 in a peroxisome proliferator-activated receptor (PPAR) γ-dependent manner. The expression of APH-1α/1β and PS1 ultimately determined the production and deposition of β-amyloid protein (Aβ), an effect that potentially contributes to the pathogenesis of AD.