Prostaglandin I2 upregulates the expression of anterior pharynx-defective-1α and anterior pharynx-defective-1β in amyloid precursor protein/presenilin 1 transgenic mice.

Abstract

Cyclooxygenase-2 (COX-2) has been recently identified to be involved in the pathogenesis of Alzheimer's disease (AD). Yet, the role of an important COX-2 metabolic product, prostaglandin (PG) I2 , in the pathogenesis of AD remains unknown. Using human- and mouse-derived neuronal cells as well as amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice as model systems, we elucidated the mechanism of anterior pharynx-defective (APH)-1α and pharynx-defective-1β induction. In particular, we found that PGI2 production increased during the course of AD development. Then, PGI2 accumulation in neuronal cells activates PKA/CREB and JNK/c-Jun signaling pathways by phosphorylation, which results in APH-1α/1β expression. As PGI2 is an important metabolic by-product of COX-2, its suppression by NS398 treatment decreases the expression of APH-1α/1β in neuronal cells and APP/PS1 mice. More importantly, β-amyloid protein (Aβ) oligomers in the cerebrospinal fluid (CSF) of APP/PS1 mice are critical for stimulating the expression of APH-1α/1β, which was blocked by NS398 incubation. Finally, the induction of APH-1α/1β was confirmed in the brains of patients with AD. Thus, these findings not only provide novel insights into the mechanism of PGI2 -induced AD progression but also are instrumental for improving clinical therapies to combat AD.