APP specific bace inhibitors (ASBIs) and uses thereof

Abstract

In certain embodiments APP-specific BACE inhibitors (ASBIs) are provided as well as uses thereof. In certain embodiments methods of preventing or delaying the onset of a pre-Alzheimer's condition and/or cognitive dysfunction, and/or ameliorating one or more symptoms of a pre-Alzheimer's condition and/or cognitive dysfunction, or preventing or delaying the progression of a pre-Alzheimer's condition or cognitive dysfunction to Alzheimer's disease are provided where the method involves administering to a subject in need thereof an APP specific BACE inhibitor (ASBI) in an amount sufficient to prevent or delay the onset of a pre-Alzheimer's cognitive dysfunction, and/or to ameliorate one or more symptoms of a pre-Alzheimer's cognitive dysfunction, and/or to prevent or delay the progression of a pre-Alzheimer's cognitive dysfunction to Alzheimer's disease. In certain embodiments the ASBI is a flavonoid (e.g. galangin) or flavonoid prodrug (e.g., galangin prodrug).

What is claimed is: 
     
       1. A method of preventing or delaying the onset of a pre-Alzheimer's cognitive dysfunction, and/or preventing or delaying the progression of a pre-Alzheimer's condition or cognitive dysfunction to Alzheimer's disease, said method comprising:
 administering to a subject characterized as asymptomatic, but having a known genetic risk factor for Alzheimer's disease where said risk factor comprises an FAD mutation and/or an the APOE ε4 allele, an APP specific BACE inhibitor (ASBI) that comprises a galangin prodrug in an amount sufficient to prevent or delay the onset of a pre-Alzheimer's cognitive dysfunction, and/or to prevent or delay the progression of a pre-Alzheimer's cognitive dysfunction to Alzheimer's disease;
 wherein said galangin prodrug is characterized by the formula: 
 
 
       
         
           
           
               
               
           
         
         wherein:
 R 1 , R 2 , and R 3  are H, or a protecting group that is removed in vivo in a mammal, wherein at least one of R 1 , R 2 , and R 3  is not H; and 
 wherein, when R 1 , R 2 , and R 3  is a protecting group, said protecting group is selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
           wherein said administration produces a reduction in the CSF of levels of one or more components selected from the group consisting of total-Tau (tTau), phospho-Tau (pTau), APPneo, soluble Aβ40, pTau/Aβ42 ratio and tTau/Aβ42 ratio, and/or an increase in the CSF of levels of one or more components selected from the group consisting of Aβ42/Aβ40 ratio, Aβ42/Aβ38 ratio, sAPPα, sAPPα/sAPPβ ratio, sAPPα/Aβ40 ratio, and sAPPα/Aβ42 ratio. 
         
       
     
     
       2. A method of reducing the rate of progression of amyloidogenesis in Alzheimer's disease, said method comprising:
 administering to a subject in need thereof an APP specific BACE inhibitor (ASBI) that comprises a galangin prodrug in an amount sufficient to reduce the rate of progression of amyloidogenesis in Alzheimer's disease; 
 wherein said galangin prodrug is characterized by the formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , and R 3  are H, or a protecting group that is removed in vivo in a mammal, wherein at least one of R 1 , R 2 , and R 3  is not H; and 
 wherein, when R 1 , R 2 , or R 3  is a protecting group, said protecting group is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
       
       and
 wherein said galangin prodrug is effective to cross the blood-brain barrier, and wherein said administration produces a reduction in the CSF of levels of one or more components selected from the group consisting of total-Tau (tTau), phospho-Tau (pTau), APPneo, soluble Aβ40, pTau/Aβ42 ratio and tTau/Aβ42 ratio, and/or an increase in the CSF of levels of one or more components selected from the group consisting of Aβ42/Aβ40 ratio, Aβ42/Aβ38 ratio, sAPPα, sAPPα/sAPPβ ratio, sAPPα/Aβ40 ratio, and sAPPα/Aβ42 ratio. 
 
     
     
       3. The method of  claim 1 , wherein said APP specific BACE inhibitor is administered in a pharmaceutical formulation wherein said ASBI is the principle active component. 
     
     
       4. The method of  claim 2 , wherein said APP specific BACE inhibitor is administered in a pharmaceutical formulation wherein said ASBI is the principle active component. 
     
     
       5. The APP specific BACE inhibitor method of  claim 1 , wherein at least one of R 1 , R 2 , and R 3  is 
       
         
           
           
               
               
           
         
       
     
     
       6. The APP specific BACE inhibitor method of  claim 1 , wherein at least one of R 1 , R 2 , and R 3  is 
       
         
           
           
               
               
           
         
       
     
     
       7. The APP specific BACE inhibitor method of  claim 1 , wherein at least one of R 1 , R 2 , and R 3  is 
       
         
           
           
               
               
           
         
       
     
     
       8. The APP specific BACE inhibitor method of  claim 1 , wherein at least one of R 1 , R 2 , and R 3  is 
       
         
           
           
               
               
           
         
       
     
     
       9. The method of  claim 1 , wherein said known genetic risk comprises having the APOE ε4 allele. 
     
     
       10. The method of  claim 1 , wherein said known genetic risk comprises mutations at one or more of positions 717, 670, and 671 in the APP gene. 
     
     
       11. The method of  claim 1 , wherein said known genetic risk comprises relatives of said subject that have been diagnosed with Alzheimer's disease.