Methods for Alzheimer's Disease treatment and cognitive enhancement

Abstract

The present invention relates to compositions and methods to modulate α-secretase and/or to improve cognitive ability. The invention further relates the improved/enhanced cognitive ability in diseased individuals, particularly Alzheimer's Disease patients, and treatment thereof through increased sAPP production. Macrocyclic lactones (i.e. bryostatin class and neristatin class) are compounds preferred for use with the present composition. The present invention also provides methods for increasing the generation of non-amyloidogenic soluble APP comprising the activation of protein kinase C (PKC) by administering an effective amount of PKC activator(s).

1 . A method for enhancing cognitive ability in a human or animal, comprising administering to said human or animal a PKC activator in an amount effective for enhancing cognitive ability in a pharmaceutically acceptable carrier.  
     
     
         2 . The method of  claim 1  wherein the PKC activator selectively activates PKCα, PKCδ, and PKCε.  
     
     
         3 . The method of  claim 1 , wherein the PKC activator is a macrocyclic lactone, a benzolactam, a pyrrolidinone or a combination thereof.  
     
     
         4 . The method of  claim 3 , wherein the macrocyclic lactone is a bryostatin class or neristatin class compound.  
     
     
         5 . The method of  claim 3  wherein the PKC activator is bryostatin-1 through bryostatin 18 or neristatin-1.  
     
     
         6 . The method of  claim 1 , wherein the cognitive ability enhanced is learning, memory, or attention.  
     
     
         7 . The method of  claim 5 , wherein the animal is a primate.  
     
     
         8 . The method of  claim 5 , wherein the animal is a non-primate.  
     
     
         9 . The method of  claim 1 , wherein the amount of PKC activator administered is in an amount effective to treat cognitive impairment of a neurological disease or disorder.  
     
     
         10 . The method of  claim 9 , wherein the neurological disease is 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, Korsakow's disorder, or attention deficit hyperactivity disorder.  
     
     
         11 . The method of  claim 9 , wherein the disorder is associated with age, electro-convulsive therapy or brain damage.  
     
     
         12 . The method of  claim 11 , wherein the brain damage was caused by stroke, an anesthetic accident, head trauma, hypoglycemia, carbon monoxide poisoning, lithium intoxication or a vitamin deficiency.  
     
     
         13 . The method of  claim 1 , wherein the PKC activator is administered in an amount effected to cause an increase in sAPP.  
     
     
         14 . A method for altering cellular modulation of ion channels comprising administering a PKC activator in an amount effective for altering cellular modulation of ion channels and a pharmaceutically acceptable carrier.  
     
     
         15 . The method of  claim 14  wherein, said modulation is in vivo or in vitro modulation.  
     
     
         16 . The method of  claim 15 , wherein said ion channel is a K +  or Ca ++ channel.  
     
     
         17 . A method for treating neurotumors comprising administering macrocyclic lactone in an amount effective to treat said neurotumors and a pharmaceutically acceptable carrier.  
     
     
         18 . The method of  claim 17  wherein, the macrocyclic lactone is a bryostatin class or neristatin class compound.  
     
     
         19 . A method for modulating sAPP comprising administering a macrocyclic lactone in an amount effective to modulate sAPP and a pharmaceutically acceptable carrier.  
     
     
         20 . The method of  claim 19  wherein, the macrocyclic lactone activates PKC.  
     
     
         21 . The method of  claim 19  wherein, the macrocyclic lactone is a bryostatin class or a neristatin class compound.  
     
     
         22 . The method of  claim 19  wherein, the macrocyclic lactone is bryostatin-1 through bryostatin 18, or neristatin-1.  
     
     
         23 . A method for modulating α-secretase comprising administering a macrocyclic lactone in an amount effective to modulate α-secretase and a pharmaceutically suitable carrier.  
     
     
         24 . The method of  claim 23  wherein, the macrocyclic lactone is a bryostatin class or a neristatin class compound.  
     
     
         25 . The method of  claim 23  wherein, the macrocyclic lactone is bryostatin-1 through bryostatin 18, or neristatin-1.  
     
     
         26 . The method of  claim 23  wherein, the macrocyclic lactone is administered in vivo or in vitro.  
     
     
         27 . The method of  claim 23  wherein, the modulation of α-secretase reduces amyloid plaque formation and enhances cognitive ability in a patient with Alzheimer's Disease.  
     
     
         28 . A method for treating Alzheimer's Disease comprising administering to a patient a macrocyclic lactone in an amount effective to treat Alzheimer's Disease and a pharmaceutically acceptable carrier.  
     
     
         29 . A method for treating Alzheimer's Disease comprising administering bryostatin-1 to a patient in an amount effective to treat Alzheimer's Disease and a pharmaceutically acceptable carrier.  
     
     
         30 . A method for enhancing cognitive ability in a human or animal, comprising administering to said human or animal a bryostatin or a neristatin class compound in an amount effective for enhancing cognitive ability in a pharmaceutically acceptable carrier.  
     
     
         31 . A method for enhancing cognitive ability in a human or animal, comprising administering to said human or animal bryostatin-1 in an amount effective for enhancing cognitive ability in a pharmaceutically acceptable carrier.  
     
     
         32 . A method comprising the modulation of α-secretase through the administration of a pharmaceutically effective amount of a bryostatin or a neristatin class compound and a pharmaceutically acceptable carrier.  
     
     
         33 . A method for modulating α-secretase comprising administering bryostatin-1 in an amount effective to modulate α-secretase and a pharmaceutically acceptable carrier.  
     
     
         34 . A method for providing a neuroprotective effect for cell comprising administering a bryostatin or neristatin class compound in an amount effective to provided a neuroprotective effect for cells which suffer from a hypoxic event and a pharmaceutically acceptable carrier.  
     
     
         35 . A method for providing a neuroprotective effect for cell comprising administering bryostatin-1 in an amount effective to provided a neuroprotective effect for cells which suffer from a hypoxic event and a pharmaceutically acceptable carrier.  
     
     
         36 . A method for the reduction of amyloid plaque formation comprising administering bryostatin-1 in an amount effective to reduce amyloid plaque formation and a pharmaceutically acceptable carrier.