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 alleviating the negative effects of a neurological disorder or neurodegenerative disease stemming from the aberrant expression, production, or formation of amyloid precursor protein (APP) in a subject comprising administering to a subject suffering from said d

[ What is claimed is:] [1.] A method of alleviating the negative effects of a neurological disorder or neurodegenerative disease stemming from the aberrant expression, production, or formation of amyloid precursor protein (APP) in a subject comprising administering to a subject suffering from said disorder or disease an effective amount of an antagonist of a .beta.-adrenergic receptor that is coupled to the cellular levels of cAMP. [16.] A method of alleviating the negative effects of a neurological disorder or neurodegenerative disease stemming from aberrant expression, production, or formation of amyloid precursor protein, in a subject in need thereof, comprising administering a protein kinase A or protein kinase C signaling agent. The method of claim 16 in which the agent is phorbol ester, indolactam, mezerin, diacylglycerol, cAMP, cGMP, related analogs, forskolin, activators of adenylate guanylate cyclase, inhibitors of adenylate guanylate cyclase, modulators of calcium channels, modulators of potassium channels, G-proteins, or combinations thereof. The method of claim 16 in which administration of the signaling agent reduces cyclic AMP levels. A method of stimulating the processing of amyloid precursor protein comprising administering a phorbol ester, a diacylglycerol or a combination thereof, wherein said administration stimulates the processing of amyloid precursor protein.