Regulation of GSK-3alpha activity for the treatment or prevention of Alzheimer's disease

Abstract

Provided is a novel use of therapeutic concentrations of an inhibitor of glycogen synthase kinase-3 (GSK-3), including lithium or any other GSK-3 inhibitor, to block, reduce or inhibit processing of amyloid precursor proteins to beta-amyloid (Aβ) peptides, which are now believed to be the principal cause of Alzheimer's disease, thereby providing methods useful for the prevention, inhibition or reversal of the disease. Also provided are methods of using agents that specifically target the α isoform of GSK-3, which is responsible for APP processing, making such selective GSK-3α-specific inhibitors especially useful in the treatment, prevention, and possible reversal of Alzheimer's disease. Further provided are kits and screening methods associated with the present methods.

1 . A method of inhibiting or reducing symptoms of a condition, disease or disorder in a patient mediated by GSK-3 or GSK-3α activity, exclusive of Alzheimer's disease, the method comprising the steps of:
 administering to the patient a therapeutically effective composition, comprising a pharmaceutically acceptable amount of a GSK-3 inhibitor or GSK-3α-specific inhibitor, respectively;   measuring the blocking, inhibiting or reducing production of Aβ amyloid peptides in the patient following administering the pharmaceutically acceptable amount of the GSK-3 inhibitor or GSK-3α-specific inhibitor, respectively; and   determining that the administered inhibitor is sufficient to block or inhibit GSK-3 or GSK-3α activity in the patient, such that measured formation of Aβ amyloid peptides in the patient is reduced in the range of 30% to 60%.   
     
     
         2 . The method of  claim 1 , wherein the patient is a mammal. 
     
     
         3 . The method of  claim 2 , wherein the mammal is human. 
     
     
         4 . The method of  claim 1 , wherein the GSK-3 inhibitor or GSK-3α-specific inhibitor, respectively, comprises lithium or a salt thereof or kenpaullone. 
     
     
         5 . The method of  claim 1 , wherein the GSK-3 inhibitor comprises a composition exclusive of lithium or kenpaullone. 
     
     
         6 . The method of  claim 1 , wherein the patient's requirement for other medication to treat the condition, disease or disorder and the patient's symptoms related thereto is reduced. 
     
     
         7 . The method of  claim 1 , further comprising:
 measuring the blocking, inhibiting or reducing production of soluble Aβ 40  and Aβ 42  peptide levels in the patient following administering the pharmaceutically acceptable amount of the GSK-3 inhibitor or GSK-3α_inhibitor; and   determining that the administered inhibitor is effective for inhibiting or reducing symptoms of the condition, disease or disorder in the patient, such that measured soluble or insoluble Aβ 40  and Aβ 42  peptide levels are reduced in the range of 30% to 60%.   
     
     
         8 . The method of  claim 1 , wherein blocking, inhibiting or reducing GSK-3α activity disrupts γ-secretase cleavage of APP, without inhibiting Notch processing. 
     
     
         9 . The method comprising treating in vitro the condition, disease or disorder of the patient of  claim 1 , wherein the condition, disease or disorder is mediated by GSK-3 or GSK-3α activity, respectively, in brain cells or tissues, the treatment comprising exposing the brain cells or tissue to the therapeutically effective composition, comprising a pharmaceutically acceptable amount of GSK-3 inhibitor or GSK-3α-specific inhibitor, respectively, that is sufficient to block or inhibit activity of GSK-3 or GSK-3α, respectively. 
     
     
         10 . The method of  claim 9 , wherein the GSK-3 inhibitor or GSK-3α-specific inhibitor, respectively, comprises lithium or a salt thereof or kenpaullone. 
     
     
         11 . The method of  claim 9 , wherein the brain cells or tissues are from a non-Alzheimer's disease patient. 
     
     
         12 . A method for stabilizing a patient susceptible to a condition, disease or disorder in a patient mediated by GSK-3 or GSK-3α activity, the method comprising the steps of:
 administering to the patient a therapeutically effective composition, comprising a pharmaceutically acceptable amount of a GSK-3 inhibitor or GSK-3α-specific inhibitor, respectively, based upon predetermined effective amounts of each composition; and   determining that the administered inhibitor is sufficient to block or inhibit GSK-3 or GSK-3α activity in the patient.   
     
     
         13 . The method of  claim 12 , wherein the patient is susceptible to Alzheimer's disease. 
     
     
         14 . The method of  claim 12 , wherein the patient is a mammal. 
     
     
         15 . The method of  claim 14 , wherein the mammal is human. 
     
     
         16 . The method of  claim 1 , wherein the GSK-3 inhibitor or GSK-3α-specific inhibitor, respectively, comprises lithium or a salt thereof or kenpaullone. 
     
     
         17 . The method of  claim 1 , wherein the GSK-3 inhibitor comprises a composition exclusive of lithium or kenpaullone. 
     
     
         18 . The method of  claim 12 , wherein stabilizing the patient comprises delaying onset of symptoms or preventing the condition, disease or disorder mediated by GSK-3 or GSK-3αactivity. 
     
     
         19 . A kit for selectively inhibiting GSK-3 or GSK-3α activity, respectively, comprising a therapeutically effective composition, comprising a pharmaceutically acceptable amount of GSK-3 inhibitor or GSK-3α-specific inhibitor, respectively, that is sufficient to block or inhibit activity of GSK-3 or GSK-3α, respectively, and an instructional material regarding the use thereof to treat a condition, disease or disorder mediated by GSK-3 or GSK-3α activity in a patient, or in brain cells or tissues of a patient. 
     
     
         20 . A method of detecting a composition of matter that blocks, inhibits or reduces GSK-3 or GSK-3α kinase activity, comprising testing the composition in brain cells or brain tissue in vitro from a subject for its capability of blocking, reducing or inhibiting the processing of amyloid precursor proteins to β-amyloid peptides of the type characterizing Alzheimer's disease and comparing the effectiveness of such composition for disrupting the production of the Aβ peptides with the effectiveness of a known GSK-3 inhibitor, and selecting the composition having such effective blocking, inhibiting or reducing capability. 
     
     
         21 . The method of  claim 20 , further comprising testing the composition in brain cells or brain tissue from a subject for GSK-3 or GSK-3α specificity; and testing its capability of blocking, reducing or inhibiting γ-secretase mediated-APP processing, then comparing effectiveness of such composition for disrupting APP processing with effectiveness of the known GSK-3αinhibitors; and selecting the composition having effective blocking, inhibiting or reducing capability. 
     
     
         22 . The method of  claim 21 , further comprising testing the composition for its capability of blocking or inhibiting GSK-3β activity, and selecting the composition that blocks, inhibits or reduces GSK-3α activity without affecting GSK-3β activity.