It has been discovered that the stimulation of beta-
adrenergic receptors, which activate cAMP formation, give rise to increased APP and GFAP synthesis in astrocytes. Hence, the
in vitro or
in vivo exposure of neuronal cells to certain compositions comprising beta-
adrenergic receptor ligands or agonists, including, e.g., norepinephrine, isoproterenol and the like, increases APP mRNA transcription and consequent APP
overproduction. These increases are blocked by beta-
adrenergic receptor antagonists, such as
propranolol. The
in vitro or
in vivo treatment of these cells with 8Br-cAMP,
prostaglandin E2 (PG E2),
forskolin, and
nicotine ditartrate also increased APP synthesis, including an increase in mRNA and holoprotein levels, as well as an increase in the expression of
glial fibrillary acidic protein (GFAP). Compositions and methods are disclosed of regulating APP overexpression and mediating reactive astrogliosis through cAMP signaling or the activation of beta-adrenergic receptors. It has further been found that the increase in APP synthesis caused by 8Br-cAMP, PG E2, or
forskolin is inhibited by immunosuppressants, immunophilin ligands, or anti-inflammatory agents, such as
cyclosporin A, and FK-506 (
tacrolimus), as well as
ion-channel modulators, including
ion chelating agents such as EGTA, or
calcium /
calmodulin kinase inhibitors, such as KN93. The present invention has broad implications in the alleviation, treatment, or prevention of neurological disorders and neurodegenerative diseases, including Alzheimer's
Disease.