The Protective Effects of Up-Regulating Prostacyclin Biosynthesis on Neuron Survival in Hippocampus.

Cellular arachidonic acid (AA), an unsaturated fatty acid found ubiquitously in plasma membranes, is metabolized to different prostanoids, such as prostacyclin (PGI) and prostaglandin E (PGE), by the three-step reactions coupling the upstream cyclooxygenase (COX) isoforms (COX-1 and COX-2) with the corresponding individual downstream synthases. While the vascular actions of these prostanoids are well-characterized, their specific roles in the hippocampus, a major brain area for memory, are poorly understood. The major obstacle for its understanding in the brain was to mimic the biosynthesis of each prostanoid. To solve the problem, we utilized Single-Chain Hybrid Enzyme Complexes (SCHECs), which could successfully control cellular AA metabolites to the desired PGI or PGE. Our in vitro studies suggested that neurons with higher PGI content and lower PGE content exhibited survival protection and resistance to Amyloid-β-induced neurotoxicity. Further extending to an in vivo model, the hybrid of PGI-producing transgenic mice and Alzheimer's disease (AD) mice showed restored long-term memory. These findings suggested that the vascular prostanoids, PGI and PGE, exerted significant regulatory influences on neuronal protection (by PGI), or damage (by PGE) in the hippocampus, and raised a concern that the wide uses of aspirin in cardiovascular diseases may exert negative impacts on neurodegenerative protection. Graphic Abstract Our study intended to understand the crosstalk of prostanoids in the hippocampus, a major brain area impacted in AD, by using hybrid enzymes to redirect the synthesis of prostanoids to PGE and PGI, respectively. Our data indicated that during inflammation, the vascular mediators, PGI and PGE, exerted significant regulatory influences on neuronal protection (by PGI), or damage (by PGE) in the hippocampus. These findings also raised a concern that the widely uses of non-steroidal anti-inflammatory drugs in cardiovascular diseases may exert negative impacts on neurodegenerative protection.