Regulation of APP synthesis and secretion by neuroimmunophilin ligands and cyclooxygenase inhibitors

Abstract

We and others previously showed that both the synthesis of the amyloid precursor protein (APP) and its processing (i.e., to amyloidogenic A beta peptides; soluble nonamyloidogenic APPs; and other APP fragments) are regulated by neurotransmitters. Transmitters that elevate cellular cAMP levels (like norepinephrine and prostaglandins, which act on beta-adrenergic receptors and prostaglandin E2 receptors respectively) enhance APP synthesis and the formation of amyloidogenic APP holoprotein. Transmitters that stimulate phosphatidylinositol hydrolysis (by activating muscarinic m1 or m3 receptors, serotoninergic 5HT2a or 5HT2c receptors, or metabotropic glutamate receptors of subtypes 1 or 5) increase the conversion of APP to soluble APPs, and decrease the formation of A beta. These findings suggest that drugs that regulate the activity of neurotransmitter receptors might be useful in preventing the excessive formation of A beta or other amyloid precursors in Alzheimer's disease. We now show that neuroimmunophilin ligands (like cyclosporin A or FK-506) and nonsteroidal antiinflammatory agents (NSAIDs), including cyclooxygenase (COX)-2 inhibitors, can also prevent APP overexpression and the overproduction of amyloidogenic peptides. We observe that the enhancement of APP overexpression by prostaglandin E2 is inhibited by neuroimmunophilin ligands like cyclosporin A or FK-506 (tacrolimus). We also find that the NSAIDs, which reduce prostaglandin synthesis by inhibiting COX-1 and -2 enzymes, might also be expected to lower APP levels. Our present data confirm that these drugs, as well as drugs that selectively inhibit COX-2, reduce the levels of amyloidogenic APP holoprotein in cultured neurons or in cultured astrocytes. We previously showed that elevations in cAMP, perhaps generated in response to prostaglandins, can suppress APPs secretion. The NSAIDs and COX inhibitors also increased levels of soluble APPs in the media of cultured astrocytes and neurons, perhaps acting by inhibition of prostaglandin production. Since APP holoprotein can be amyloidogenic, while APPs may be neurotrophic, our findings suggest that some neuroimmunophilin ligands, NSAIDs and COX-2 inhibitors might suppress amyloid formation and enhance neuronal regeneration in Alzheimer's disease.