Prevention and treatment of amyloid-associated disorders

Abstract

The present invention provides a method of assaying for and arresting, preventing and/or reversing the impairment of central and peripheral nervous system function comprising reducing β-amyloid plaque burden by the administration of compounds that reduce apoE expression. The compounds used in the method of the invention may be: 1) inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase; 2) inhibitors of cholesterol biosynthesis; 3) inhibitors of protein isoprenylation, specifically geranylgeranylation; and/or 4) inhibitors of NF-κB activation or function. Assays for compounds with inhibit apoE expression from microglial cells are also disclosed.

What is claimed is:  
     
         1 . An assay to identify a compound which alters apolipoprotein E release in a glial cell, comprising the steps of: 
 culturing glial cells which express apolipoprotein E at a known level;    contacting the cells with a compound to be tested; and    determining effects of the compound on the apolipoprotein E expression.    
     
     
         2 . The assay of  claim 1 , wherein the effect of the compound is determined by comparing the effect with a control culture which is not contacted with the compound.  
     
     
         3 . The assay of  claim 1 , wherein the compound to be tested suppresses NF-κB activation, and wherein suppression is identified using an-NF-κB reporter construct.  
     
     
         4 . A method for modulating apolipoprotein E expression, comprising the steps of: 
 analyzing glial cells from the central nervous system of a patient;    determining the level of expression of apolipoprotein E from the glial cells;    administering a compound in an amount effective to reduce apolipoprotein expression.    
     
     
         5 . The method of  claim 4  wherein the glial cells are derived from the cerebrospinal fluid of a human patient and the compound is administered to that human patient.  
     
     
         6 . A method for reducing the level of β-amyloid plaque in the brain tissue of a mammalian host, said method comprising: 
 administering to said mammalian host a compound in an amount effective to reduce the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in brain tissue,  
 wherein the lowered HMG CoA reductase activity results in reduced release of apolipoprotein E in brain tissue.  
 
     
     
         7 . The method of  claim 6 , wherein the compound is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor selected from the group consisting of: mevastatin, lovastatin, compactin, nisvastatin, atorvastatin, pravastatin, simvastatin, and fluvastatin, and 
 wherein the reduced apoE release results from suppression of β-amyloid stimulated release of apoE from cells selected from the group consisting of microglial cells and astrocytes.    
     
     
         8 . The method of  claim 6 , wherein the compound is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor selected from the group consisting of: mevastatin, lovastatin, compactin, nisvastatini, atorvastatin, pravastatin, simvastatin, and fluvastatin, and 
 wherein the reduced apoE release results from suppression of interleukin-6 stimulated release of apoE from cells selected from the group consisting of microglial cells and astrocytes.    
     
     
         9 . The method of  claim 6 , wherein the compound reduces 3-hydroxy-3-methylglutaryl coenzyme A reductase activity by 30 and 80%, and wherein apolipoprotein E release levels are reduced by 20-80%.  
     
     
         10 . A method for reducing the level of β-amyloid plaque burden in the brain tissue of a mammalian host, said method comprising: 
 administering to said mammalian host a compound in an amount effective to suppress cholesterol biosynthesis,  
 wherein the suppression of cholesterol biosynthesis results in reduced release of apolipoprotein E in the brain tissue.  
 
     
     
         11 . The method of  claim 10 , wherein the compound is an inhibitor of cholesterol biosynthesis selected from the group consisting of mevalonate pyrophosphate decarboxylase inhibitors, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase inhibitors, squalene synthase inhibitors, and squalene epoxidase inhibitors; 
 wherein the reduced apoE release results from suppression of β-amyloid stimulated release of apoE from cells selected from the group consisting of microglial cells and astrocytes.    
     
     
         12 . The method of  claim 11 , wherein the compound reduces cholesterol biosynthesis by 20 and 80%, and wherein the compound reduces the apolipoprotein E release levels by 20-90%.  
     
     
         13 . The method of  claim 12 , wherein the compound reduces apolipoprotein E release levels by 60-80%.  
     
     
         14 . A method for suppressing β-amyloid stimulated release of apolipoprotein E, said method comprising: 
 administering to a mammalian host a compound in an amount effective to suppress protein isoprenylation,  
 wherein the suppressed protein isoprenylation results in reduced release of apolipoprotein E in the brain tissue.  
 
     
     
         15 . The method of  claim 14 , wherein the compound suppresses isoprenylation selected from the group consisting of: geranylation, geranylgeranylation, and famesylation.  
     
     
         16 . The method of  claim 15 , wherein the compound suppresses geranylgeranylation, and wherein the compound suppresses the activity of an enzyme selected from the group consisting of geranylgeranyldipiphosphate (GGPP) synthase and geranylgeranyl protein transferase (GGPTase).  
     
     
         17 . The method of  claim 15 , wherein the compound is selected from the group consisting of FPT-II and GGTI-286.  
     
     
         18 . A method for reducing the level of β-amyloid plaque in the brain tissue of a mammalian host, said method comprising: 
 administering to said mammalian host a compound in an amount effective to reduce the activation of NF-κB in brain tissue,  
 wherein the lowered NF-κB activation results in reduced release of apolipoprotein E in brain tissue.  
 
     
     
         19 . The method of  claim 18 , wherein the compound is an inhibitor of a kinase involved in phosphorylation of IκB.  
     
     
         20 . The method of  claim 19 , wherein the compound is sodium salicylate.  
     
     
         21 . The method of  claim 18 , wherein the compound increases the rate of ubiquination of phosphorylated IκB in brain tissue.  
     
     
         22 . A method for treating a mammal with an amyloid-associated disorder, said method comprising: 
 administering to said mammal a compound in an amount effective to reduce the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in brain tissue;    wherein the lowered HMG CoA reductase activity results in reduced apolipoprotein E release and reduced levels of amyloid plaques in the brain tissue.    
     
     
         23 . The method of  claim 22  wherein the amyloid-associated disorder is a disorder selected from the group consisting of AD, CAA, and a prion-mediated disorder, and 
 wherein the compound is selected from the group consisting of: mevastatin, lovastatin, compactin, nisvastatin, atorvastatin, pravastatin, simvastatin, and fluvastatin.  
 
     
     
         24 . The method of  claim 22  wherein the amyloid-associated disorder is AD and the mammal has at least one apoE4 allele.  
     
     
         25 . The method of  claim 22 , wherein the amyloid-associated disorder is AD and the compound is an inhibitor of cholesterol biosynthesis, and 
 wherein the compound is selected from the group consisting of mevalonate pyrophosphate decarboxylase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase, squalene synthase inhibitors, and squalene epoxidase inhibitors.    
     
     
         26 . A method for treating a mammal with an amyloid-associated disorder, said method comprising: 
 administering to said mammal a compound in an amount effective to reduce the activation of NF-κB in brain tissue,    wherein the lowered NF-κB activation results in reduced release of apolipoprotein E release and reduced levels of amyloid plaques in the brain tissue.    
     
     
         27 . The method of  claim 26  wherein the amyloid-associated disorder is a disorder selected from the group consisting of AD, CAA, and a prion-mediated disorder, and 
 wherein the compound is a kinase inhibitor.  
 
     
     
         28 . The method of  claim 27 , wherein the compound is sodium salicylate.  
     
     
         29 . The method of  claim 26  wherein the amyloid-associated disorder is AD and the mammal has at least one apoE4 allele.  
     
     
         30 . A method for treating a mammal with an amyloid-associated disorder, said method comprising: 
 administering to said mammal a compound in an amount effective to inhibit protein isoprenylation;    wherein the activity of compound decreases protein isoprenylation and suppresses release of apolipoprotein E from glial cells in brain tissue.    
     
     
         31 . The method of  claim 30 , wherein the compound inhibits geranylgeranylation.  
     
     
         32 . A method for preventing the formation of amyloid plaques in the brain of a mammal at risk for an amyloid-associated disorder, said method comprising: 
 administering to said mammal a compound in an amount effective to reduce the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase;    wherein the lowered HMG CoA reductase activity results in reduced apolipoprotein E release from glial cells and suppresses formation of amyloid plaques in brain tissue.    
     
     
         33 . The method of  claim 32 , wherein the mammal at risk for AD is a human and the compound is an inhibitor of cholesterol biosynthesis selected from the group consisting of mevalonate pyrophosphate decarboxylase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase, squalene synthase inhibitors, and squalene epoxidase inhibitors.  
     
     
         34 . A method for preventing the formation of amyloid plaques in the brain of a mammal at risk for an amyloid-associated disorder, said method comprising: 
 administering to said mammal a compound in an amount effective to suppress β-amyloid stimulated release of apolipoprotein E.