Assays and methods of diagnosis and treatment based on use of sodium channels as targets for amyloid beta or its aggregates

Abstract

Among other things, assays and methods of diagnosis and treatment of disease (e.g., Alzheimer's disease) based on the surprising observation of an interaction between amyloid β or its aggregates with the sodium channel are provided. In particular, methods to identify compounds that modulate this interaction are provided, as well as methods of diagnosis and treatment that are based on this interaction.

What is claimed is:  
     
         1 . A method for identifying compounds that modulate the interaction of amyloid β or its aggregates with a sodium channel, said method comprising: 
 (a) obtaining a cell that comprises a sodium channel;  
 (b) contacting said sodium channel with amyloid β or its aggregates in the presence and absence of a test compound; and  
 (c) determining the activity of said sodium channel in the presence of said test compound as compared with in the absence, wherein a test compound that impacts activity is considered a modulator of the interaction of amyloid β or its aggregates with said sodium channel.  
 
     
     
         2 . The method of  claim 1 , wherein said cell is a neuronal cell.  
     
     
         3 . The method of  claim 1 , wherein said cell is a non-neuronal cell.  
     
     
         4 . The method of  claim 1 , wherein said activity is determined by a method selected from the group consisting of examining resting membrane potential, examining action potential, and measuring the fast inward sodium current.  
     
     
         5 . The method of  claim 1 , further comprising a step of manufacturing a composition comprising a modulator identified according to step (c) in a pharmaceutically acceptable carrier.  
     
     
         6 . The method of  claim 1 , further comprising a step of treating Alzheimer's disease with a composition comprising a modulator identified according to step (c).  
     
     
         7 . A compound identified as a modulator according to  claim 1 .  
     
     
         8 . A composition comprising a compound according to  claim 7  in a pharmaceutically acceptable carrier.  
     
     
         9 . A method of using a compound according to  claim 7  in the manufacture of a medicament for the prevention, treatment, or reversal of Alzheimer's disease in a mammal.  
     
     
         10 . A method for identifying compounds that modulate the interaction of amyloid β or its aggregates with a sodium channel, said method comprising: 
 (a) obtaining a first cell that produces amyloid β or its aggregates;  
 (b) obtaining a second cell comprising a sodium channel;  
 (c) contacting said second cell with said first cell in the presence and absence of a test compound; and  
 (d) determining the activity of said sodium channel in the presence of said test compound as compared with in the absence, wherein a test compound that impacts activity is considered a modulator of the interaction of amyloid β or its aggregates with said sodium channel.  
 
     
     
         11 . The method of  claim 10 , wherein one of said first and second cells is a neuronal cell and the other is a non-neuronal cell.  
     
     
         12 . The method of  claim 10 , wherein both said first and second cells are either a neuronal cell or a non-neuronal cell.  
     
     
         13 . The method of  claim 10 , wherein said activity is determined by a method selected from the group consisting of examining resting membrane potential, examining action potential, and measuring the fast inward sodium current.  
     
     
         14 . The method of  claim 10 , further comprising a step of manufacturing a composition comprising a modulator identified according to step (d) in a pharmaceutically acceptable carrier.  
     
     
         15 . The method of  claim 10 , further comprising a step of treating Alzheimer's disease with a composition comprising a modulator identified according to step (d).  
     
     
         16 . A compound identified as a modulator according to  claim 10 .  
     
     
         17 . A composition comprising a compound according to  claim 16  in a pharmaceutically acceptable carrier.  
     
     
         18 . A method of using a compound according to  claim 16  in the manufacture of a medicament for the prevention, treatment, or reversal of Alzheimer's disease in a mammal.  
     
     
         19 . A method for identifying compounds that modulate the interaction of amyloid β or its aggregates with a sodium channel, said method comprising: 
 (a) obtaining a composition comprising a purified sodium channel;  
 (b) contacting said sodium channel with amyloid β or its aggregates in the presence and absence of a test compound; and  
 (c) determining the activity of said sodium channel in the presence of said test compound as compared with in the absence, wherein a test compound that impacts activity is considered a modulator of the interaction of amyloid β or its aggregates with said sodium channel.  
 
     
     
         20 . The method of  claim 19 , wherein said activity is determined by a method selected from the group consisting of examining resting membrane potential, examining action potential, and measuring the fast inward sodium current.  
     
     
         21 . The method of  claim 19 , further comprising a step of manufacturing a composition comprising a modulator identified according to step (c) in a pharmaceutically acceptable carrier.  
     
     
         22 . The method of  claim 19 , further comprising a step of treating Alzheimer's disease with a composition comprising a modulator identified according to step (c).  
     
     
         23 . A compound identified as a modulator according to  claim 19 .  
     
     
         24 . A composition comprising a compound according to  claim 23  in a pharmaceutically acceptable carrier.  
     
     
         25 . A method of using a compound according to  claim 23  in the manufacture of a medicament for the prevention, treatment, or reversal of Alzheimer's disease in a mammal.  
     
     
         26 . A method for diagnosing Alzheimer's disease in a mammal suspected of having Alzheimer's disease, said method comprising the step of measuring the activity of a sodium channel in a cell of said mammal, wherein reduced activity of said sodium channel is correlated with the existence of an Alzheimer's disease state.  
     
     
         27 . The method of  claim 26 , wherein said cell is a neuronal cell.  
     
     
         28 . The method of  claim 26 , wherein said cell is a non-neuronal cell.  
     
     
         29 . The method of  claim 26 , wherein said activity is determined by a method selected from the group consisting of examining resting membrane potential, examining action potential, and measuring the fast inward sodium current.  
     
     
         30 . The method of  claim 26 , further comprising a step of measuring the amounts of amyloid β or its aggregates in said cell or in extracellular fluid from said mammal that contacts the cell, wherein the presence of amyloid β or its aggregates in said cell or fluid is correlated with the existence of an Alzheimer's disease state.  
     
     
         31 . A method of screening a mammal for susceptibility to Alzheimer's disease, comprising the steps of: 
 (a) isolating a cell from said mammal, said cell comprising a sodium channel; and    (b) measuring activity of said sodium channel in the absence and in the presence of amyloid β or its aggregates;    wherein reduced activity of said sodium channel in the presence of amyloid β or its aggregates as compared to in the absence is correlated with a susceptibility to developing Alzheimer's disease.    
     
     
         32 . The method of  claim 31 , wherein said cell is a neuronal cell.  
     
     
         33 . The method of  claim 31 , wherein said cell is a non-neuronal cell.  
     
     
         34 . The method of  claim 31 , wherein said activity is determined by a method selected from the group consisting of examining resting membrane potential, examining action potential, and measuring the fast inward sodium current.  
     
     
         35 . A method for diagnosing prion disease in a mammal suspected of having prion disease, said method comprising the step of measuring the activity of a sodium channel in a cell of said mammal, wherein reduced activity of said sodium channel is correlated with the existence of a prion disease state.  
     
     
         36 . The method of  claim 35 , wherein said cell is a neuronal cell.  
     
     
         37 . The method of  claim 35 , wherein said cell is a non-neuronal cell.  
     
     
         38 . The method of  claim 35 , wherein said activity is determined by a method selected from the group consisting of examining resting membrane potential, examining action potential, and measuring the fast inward sodium current.  
     
     
         39 . A method for preventing, treating, or reversing Alzheimer's disease in a mammal, said method comprising contacting a sodium channel of said mammal with a compound that protects said sodium channel from a reduction in sodium channel activity due to amyloid β or its aggregates.  
     
     
         40 . The method of  claim 35 , wherein said activity is determined by a method selected from the group consisting of examining resting membrane potential, examining action potential, and measuring the fast inward sodium current.  
     
     
         41 . A method for preventing, treating, or reversing prion disease in a mammal, said method comprising contacting a sodium channel of said mammal with a compound that protects said sodium channel from a reduction in sodium channel activity due to amyloid β or its aggregates.  
     
     
         42 . The method of  claim 41 , wherein said activity is determined by a method selected from the group consisting of examining resting membrane potential, examining action potential, and measuring the fast inward sodium current.  
     
     
         43 . A method for preventing, treating, or reversing Alzheimer's disease in a mammal, said method comprising contacting a sodium channel of said mammal with a compound that opens said sodium channel.  
     
     
         44 . A method for preventing, treating, or reversing prion disease in a mammal, said method comprising contacting a sodium channel of said mammal with a compound that opens said sodium channel.