초록 ▼

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 a

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 E.sub.2 (PG E.sub.2), 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 E.sub.2, forskolin, or nicotine ditartrate is inhibited by immunosuppressants 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.

대표청구항 ▼

[ What is claimed is:] [1.] A method of modulating expression, production, or formation of amyloid precursor protein (APP) in a subject comprising administering to the subject an effective amount of cyclic adenosine monophosphate (cAMP), an analog of cAMP, a substance that is a ligand, an agonist, o

[ What is claimed is:] [1.] A method of modulating expression, production, or formation of amyloid precursor protein (APP) in a subject comprising administering to the subject an effective amount of cyclic adenosine monophosphate (cAMP), an analog of cAMP, a substance that is a ligand, an agonist, or an antagonist of a receptor that is coupled to cellular levels of cAMP or to ion channels, a compound that regulates ion channels or the nuclear actions of cAMP, or a compound that regulates the activity of protein kinase A. [18.] A method of modulating amyloid precursor protein (APP) expression in a subject comprising administering to the subject an effective amount of a substance that regulates APP promoter activity. [19.] The method of claim 18 in which said substance stimulates APP promoter activity.