Methods for Alzheimer's disease treatment and cognitive enhance

Abstract

The present invention relates to compositions comprising a combination of PKC activators and PKC inhibitors and methods to modulate α-secretase activity; improve or enhance cognitive ability; and/or reduce neurodegeneration in individuals suffering from diseases that impair cognitive ability, particularly Alzheimer's Disease. The invention also relates to methods for improving or enhancing cognitive ability. The present invention also provides methods for increasing the generation of non-amyloidogenic soluble APP (sAPP) comprising the activation of protein kinase C (PKC) in the brain and inhibiting PKC in peripheral tissues. Macrocyclic lactones (i.e. bryostatin class and neristatin class) are preferred PKC activators and Vitamin E is a preferred PKC inhibitor for use in the inventive composition.

1 . A composition comprising: 
 a) a PKC activator;    b) a PKC inhibitor; and    c) a pharmaceutically acceptable carrier.    
     
     
         2 . The composition of  claim 1 , wherein the PKC activator is a macrocyclic lactone.  
     
     
         3 . The composition of  claim 1 , wherein the PKC activator is a benzolactam.  
     
     
         4 . The composition of  claim 1 , wherein the PKC activator is a pyrrolidinone.  
     
     
         5 . The composition of  claim 2 , wherein the bryostatin is selected from the group consisting of bryostatin-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, and -18.  
     
     
         6 . The composition of  claim 5 , wherein the bryostatin is bryostatin-1.  
     
     
         7 . The composition of  claim 2 , wherein the macrocyclic lactone is a neristatin.  
     
     
         8 . The composition of  claim 7 , wherein the neristatin is neristatin-1.  
     
     
         9 . The composition of  claim 1 , wherein the PKC is vitamin E.  
     
     
         10 . The composition of  claim 9 , wherein the vitamin E is α-tocopherol.  
     
     
         11 . The composition of  claim 10 , wherein the α-tocopherol is present in proportion of between of between 15 and 2,000 IU per day.  
     
     
         12 . A method for reducing neurodegeneration comprising administering to a subject in need thereof the composition of  claim 1  in an amount effective to reduce neurodegeneration.  
     
     
         13 . A method for reducing neurodegeneration comprising administering to a subject in need thereof the composition of  claim 2  in an amount effective to reduce neurodegeneration.  
     
     
         14 . A method for reducing neurodegeneration comprising administering to a subject in need thereof the composition of  claim 3  in an amount effective to reduce neurodegeneration.  
     
     
         15 . A method for reducing neurodegeneration comprising administering to a subject in need thereof the composition of  claim 4  in an amount effective to reduce neurodegeneration.  
     
     
         16 . A method for reducing neurodegeneration comprising administering to a subject in need thereof the composition of  claim 5  in an amount effective to reduce neurodegeneration.  
     
     
         17 . A method for reducing neurodegeneration comprising administering to a subject in need thereof the composition of  claim 6  in an amount effective to reduce neurodegeneration.  
     
     
         18 . A method for reducing neurodegeneration comprising administering to a subject in need thereof the composition of  claim 7  in an amount effective to reduce neurodegeneration.  
     
     
         19 . A method for reducing neurodegeneration comprising administering to a subject in need thereof the composition of  claim 8  in an amount effective to reduce neurodegeneration.  
     
     
         20 . A method for reducing neurodegeneration comprising administering to a subject in need thereof the composition of  claim 9  in an amount effective to reduce neurodegeneration.  
     
     
         21 . A method for reducing neurodegeneration comprising administering to a subject in need thereof the composition of  claim 10  in an amount effective to reduce neurodegeneration.  
     
     
         22 . A method for reducing neurodegeneration comprising administering to a subject in need thereof the composition of  claim 11  in an amount effective to reduce neurodegeneration.  
     
     
         23 . The method of  claim 22 , wherein the subject suffers from a neurodegenerative disease selected from the group consisting of Alzheimer's Disease; multi-infarct dementia; the Lewy-body variant of Alzheimer's Disease with or without association with Parkinson's disease; Creutzfeld-Jakob disease; Korsakoff's disorder; and attention deficit hyperactivity disorder.  
     
     
         24 . The method of  claim 23 , wherein the neurodegenerative disease is Alzheimer's Disease.  
     
     
         25 . A method for reducing loss of cognitive ability comprising administering to a subject in need thereof the composition of  claim 1  in an amount effective to reduce loss of cognitive ability.  
     
     
         26 . A method for reducing loss of cognitive ability comprising administering to a subject in need thereof the composition of  claim 2  in an amount effective to reduce loss of cognitive ability.  
     
     
         27 . A method for reducing loss of cognitive ability comprising administering to a subject in need thereof the composition of  claim 3  in an amount effective to reduce loss of cognitive ability.  
     
     
         28 . A method for reducing loss of cognitive ability comprising administering to a subject in need thereof the composition of  claim 4  in an amount effective to reduce loss of cognitive ability.  
     
     
         29 . A method for reducing loss of cognitive ability comprising administering to a subject in need thereof the composition of  claim 5  in an amount effective to reduce loss of cognitive ability.  
     
     
         30 . A method for reducing loss of cognitive ability comprising administering to a subject in need thereof the composition of  claim 6  in an amount effective to reduce loss of cognitive ability.  
     
     
         31 . A method for reducing loss of cognitive ability comprising administering to a subject in need thereof the composition of  claim 7  in an amount effective to reduce loss of cognitive ability.  
     
     
         32 . A method for reducing loss of cognitive ability comprising administering to a subject in need thereof the composition of  claim 8  in an amount effective to reduce loss of cognitive ability.  
     
     
         33 . A method for reducing loss of cognitive ability comprising administering to a subject in need thereof the composition of  claim 9  in an amount effective to reduce loss of cognitive ability.  
     
     
         34 . A method for reducing loss of cognitive ability comprising administering to a subject in need thereof the composition of  claim 10  in an amount effective to reduce loss of cognitive ability.  
     
     
         35 . A method for reducing loss of cognitive ability comprising administering to a subject in need thereof the composition of  claim 11  in an amount effective to reduce loss of cognitive ability.  
     
     
         36 . The method of  claim 25 , wherein the subject suffers from a neurodegenerative disease selected from the group consisting of Alzheimer's Disease; multi-infarct dementia; the Lewy-body variant of Alzheimer's Disease with or without association with Parkinson's disease; Creutzfeld-Jakob disease; Korsakoff's disorder; and attention deficit hyperactivity disorder.  
     
     
         37 . The method of  claim 25 , wherein the neurodegenerative disease is Alzheimer's Disease.  
     
     
         38 . The method of  claim 25 , wherein the cognitive ability is selected from the group consisting of learning, memory and attention.  
     
     
         39 . A method for enhancing cognitive ability comprising administering to a subject in need thereof the composition of  claim 1  in an amount effective to enhance cognitive ability.  
     
     
         40 . A method for enhancing cognitive ability comprising administering to a subject in need thereof the composition of  claim 2  in an amount effective to enhance cognitive ability.  
     
     
         41 . A method for enhancing cognitive ability comprising administering to a subject in need thereof the composition of  claim 3  in an amount effective to enhance cognitive ability.  
     
     
         42 . A method for enhancing cognitive ability comprising administering to a subject in need thereof the composition of  claim 4  in an amount effective to enhance cognitive ability.  
     
     
         43 . A method for enhancing cognitive ability comprising administering to a subject in need thereof the composition of  claim 5  in an amount effective to enhance cognitive ability.  
     
     
         44 . A method for enhancing cognitive ability comprising administering to a subject in need thereof the composition of  claim 6  in an amount effective to enhance cognitive ability.  
     
     
         45 . A method for enhancing cognitive ability comprising administering to a subject in need thereof the composition of  claim 7  in an amount effective to enhance cognitive ability.  
     
     
         46 . A method for enhancing cognitive ability comprising administering to a subject in need thereof the composition of  claim 8  in an amount effective to enhance cognitive ability.  
     
     
         47 . A method for enhancing cognitive ability comprising administering to a subject in need thereof the composition of  claim 9  in an amount effective to enhance cognitive ability.  
     
     
         48 . A method for enhancing cognitive ability comprising administering to a subject in need thereof the composition of  claim 10  in an amount effective to enhance cognitive ability.  
     
     
         49 . A method for enhancing cognitive ability comprising administering to a subject in need thereof the composition of  claim 11  in an amount effective to enhance cognitive ability.  
     
     
         50 . The method of  claim 39 , wherein the subject suffers from a neurodegenerative disease selected from the group consisting of Alzheimer's Disease; multi-infarct dementia; the Lewy-body variant of Alzheimer's Disease with or without association with Parkinson's disease; Creutzfeld-Jakob disease; Korsakoff's disorder; and attention deficit hyperactivity disorder.  
     
     
         51 . The method of  claim 39 , wherein the neurodegenerative disease is Alzheimer's Disease.  
     
     
         52 . The method of  claim 39 , wherein the cognitive ability is selected from the group consisting of learning, memory and attention.  
     
     
         53 . A method for reducing loss of cognitive ability comprising the steps of administering to a subject in need thereof 
 a) a PKC activator with or without a pharmaceutically acceptable carrier; and    b) a PKC inhibitor with or without a pharmaceutically acceptable carrier;    wherein the PKC activator is administered in an amount effective to reduce loss of cognitive ability.    
     
     
         54 . The method of  claim 53 , wherein the PKC activator and PKC inhibitor are administered simultaneously.  
     
     
         55 . The method of  claim 53 , wherein the PKC activator is administered prior to administration of the PKC inhibitor.  
     
     
         56 . The method of  claim 53 , wherein the PKC inhibitor is administered prior to administration of the PKC activator.  
     
     
         57 . A method for enhancing cognitive ability comprising the steps of administering to a subject in need thereof 
 a) a PKC activator with or without a pharmaceutically acceptable carrier; and    b) a PKC inhibitor with or without a pharmaceutically acceptable carrier;    wherein the PKC activator is administered in an amount effective to enhance cognitive ability.    
     
     
         58 . The method of  claim 57 , wherein the PKC activator and PKC inhibitor is administered simultaneously.  
     
     
         59 . The method of  claim 57 , wherein the PKC activator is administered prior to administration of the PKC inhibitor.  
     
     
         60 . The method of  claim 57 , wherein the PKC inhibitor is administered prior to administration of the PKC activator.  
     
     
         61 . A method for reducing neurodegeneration comprising the steps of administering to a subject in need thereof 
 a) a PKC activator with or without a pharmaceutically acceptable carrier; and    b) a PKC inhibitor with or without a pharmaceutically acceptable carrier;    wherein the PKC activator is administered in an amount effective to reduce neurodegeneration.    
     
     
         62 . The method of  claim 61 , wherein the PKC activator and PKC inhibitor is administered simultaneously.  
     
     
         63 . The method of  claim 61 , wherein the PKC activator is administered prior to administration of the PKC inhibitor.  
     
     
         64 . The method of  claim 61 , wherein the PKC inhibitor is administered prior to administration of the PKC activator.  
     
     
         65 . The method of  claim 61 , wherein the PKC activator is a macrocyclic lactone.  
     
     
         66 . The method of  claim 61 , wherein the PKC activator is a benzolactam.  
     
     
         67 . The method of  claim 61 , wherein the PKC activator is a pyrrolidinone.  
     
     
         68 . The composition of  claim 61 , wherein the macrocyclic lactone is selected from the group consisting of bryostatin-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, and -18.  
     
     
         69 . The composition of  claim 68 , wherein the bryostatin is bryostatin-1.  
     
     
         70 . The composition of  claim 61 , wherein the macrocyclic lactone is a neristatin.  
     
     
         71 . The composition of  claim 70 , wherein the neristatin is neristatin-1.  
     
     
         72 . The composition of  claim 61 , wherein the vitamin E is in an amount between 15 and 2000 IU per day.