Method for selectively inhibiting ACAT1 in the treatment of alzheimer's disease
The present invention features methods for stimulating clearance of amyloid beta in microglia, decreasing cognitive decline associated with amyloid pathology, and treating Alzheimer's disease by selectively inhibiting the expression or activity of Acyl-CoA:Cholesterol Acyltransferase 1, but not Acyl-CoA:Cholesterol Acyltransferase 2.
1. A method for stimulating clearance of amyloid beta in microglia comprising administering to a subject in need thereof an exosome-encapsulated Acyl-CoA: Cholesterol Acyltransferase 1-selective inhibitor thereby stimulating clearance of oligomeric amyloid beta in microglia in the subject.
2. The method of claim 1 , wherein the inhibitor has an IC 50 value for Acyl-CoA:Cholesterol Acyltransferase 1 which is at least twice the corresponding IC 50 value for Acyl-CoA:Cholesterol Acyltransferase 2.
3. The method of claim 1 , wherein the inhibitor inhibits the expression or activity of Acyl-CoA: Cholesterol Acyltransferase 1.
4. The method of claim 1 , wherein the inhibitor has an IC 50 value in the range of 1 nM to 100 μM.
5. The method of claim 1 , wherein the exosome-encapsulated Acyl-CoA: Cholesterol Acyltransferase 1-selective inhibitor is administered intranasally.
6. The method of claim 1 , wherein the exosome is modified with a targeting moiety.
7. A method for decreasing cognitive decline associated with amyloid pathology comprising administering to a subject in need thereof an exosome-encapsulated Acyl-CoA: Cholesterol Acyltransferase 1-selective inhibitor thereby decreasing cognitive decline associated with amyloid pathology in the subject.
8. The method of claim 7 , wherein the inhibitor has an IC 50 value for Acyl-CoA:Cholesterol Acyltransferase 1 which is at least twice the corresponding IC 50 value for Acyl-CoA:Cholesterol Acyltransferase 2.
9. The method of claim 7 , wherein the inhibitor inhibits the expression or activity of Acyl-CoA: Cholesterol Acyltransferase 1.
10. The method of claim 7 , wherein the inhibitor has an IC 50 value in the range of 1 nM to 100 μM.
11. The method of claim 7 , wherein the exosome-encapsulated Acyl-CoA: Cholesterol Acyltransferase 1-selective inhibitor is administered intranasally.
12. The method of claim 7 , wherein the exosome is modified with a targeting moiety.
13. A method for treating Alzheimer's Disease comprising administering to a subject in need thereof an exosome-encapsulated Acyl-CoA: Cholesterol Acyltransferase 1-selective inhibitor, which stimulates clearance of oligomeric amyloid beta in microglia, thereby treating the subject's Alzheimer's Disease.
14. The method of claim 13 , wherein the inhibitor has an IC 50 value for Acyl-CoA:Cholesterol Acyltransferase 1 which is at least twice the corresponding IC 50 value for Acyl-CoA:Cholesterol Acyltransferase 2.
15. The method of claim 13 , wherein the inhibitor inhibits the expression or activity of Acyl-CoA: Cholesterol Acyltransferase 1.
16. The method of claim 13 , wherein the inhibitor has an IC 50 value in the range of 1 nM to 100 μM.
17. The method of claim 13 , wherein the exosome-encapsulated Acyl-CoA: Cholesterol Acyltransferase 1-selective inhibitor is administered intranasally.
18. The method of claim 13 , wherein the exosome is modified with a targeting moiety.