Methods and compositions for modulating Tau levels
Methods and agents for reducing a level of an acetylated Tau polypeptide in a cell are provided. Methods for treating a tauopathy in an individual are also provided. Also provided is a method for diagnosing a cognitive impairment disorder in an individual. Methods for identifying an agent suitable for treating a tauopathy are also provided.
1. A method for treating a tauopathy in an individual, the method comprising administering to the individual an effective amount of a p300 inhibitor that reduces the level of acetylated Tau in a neuron or a glial cell in the individual.
2. The method of claim 1 , wherein the p300 inhibitor is an isothiazolone-based histone acetyltransferase inhibitor.
3. The method of claim 1 , wherein the p300 inhibitor is a selective p300 inhibitor.
4. The method of claim 1 , wherein the p300 inhibitor is a p300-specific siRNA.
5. The method of claim 1 , wherein the p300 inhibitor has an IC 50 of from 1 nM to 100 nM.
6. The method of claim 1 , wherein the p300 inhibitor has an IC 50 of from 10 nM to 50 nM.
7. The method of claim 1 , wherein the p300 inhibitor is administered via oral administration.
8. The method of claim 1 , wherein the tauopathy is frontotemporal dementia, Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, Down syndrome, dementia pugilistica, inclusion-body myositis, or frontotemporal lobar degeneration.
9. The method of claim 1 , wherein the p300 inhibitor is administered in an oral dosage formulation.
10. The method of claim 9 , wherein the p300 inhibitor is formulated with one or more pharmaceutical excipients and coated with an enteric coating.
11. A method of diagnosing mild cognitive impairment (MCI) in an individual, the method comprising detecting a level of acetylated Tau polypeptide in a biological sample obtained from the individual, wherein a level of acetylated Tau polypeptide that is higher than a normal control level indicates that the individual has MCI.
12. The method of claim 11 , wherein the biological sample is cerebrospinal fluid, blood, plasma, or serum.
13. The method of claim 11 , wherein the level of acetylated Tau polypeptide is detected using an antibody that recognizes the acetylated form of Tau.
14. The method of claim 13 , wherein the level of acetylated Tau polypeptide is detected using an enzyme-linked immunosorbent assay (ELISA).
15. The method of claim 11 , comprising treating the biological sample with an enzyme inhibitor.
16. A method of diagnosing early-stage Alzheimer's disease in an individual, the method comprising detecting a level of acetylated Tau polypeptide in a biological sample obtained from the individual, wherein a level of acetylated Tau polypeptide that is higher than a normal control level indicates that the individual has early-stage Alzheimer's disease.
17. The method of claim 16 , wherein the biological sample is cerebrospinal fluid, blood, plasma, or serum.
18. The method of claim 16 , wherein the level of acetylated Tau polypeptide is detected using an antibody that recognizes the acetylated form of Tau.
19. The method of claim 18 , wherein the level of acetylated Tau polypeptide is detected using an enzyme-linked immunosorbent assay (ELISA).
20. The method of claim 16 , comprising treating the biological sample with an enzyme inhibitor.