Methods of treating neurodegenerative disease
The present disclosure provides a method of increasing the level and/or function of an Eph receptor B2 in a neuronal cell; and methods of treating an amyloid-beta-induced neurodegenerative disease in an individual. The present disclosure further provides methods of identifying an agent that increases the level and/or function of an Eph receptor B2 in a neuronal cell.
1. A method of treating an amyloid-beta-associated neurodegenerative disease in an individual, the method comprising administering to the individual a nucleic acid expression vector comprising a nucleotide sequence encoding an EphB2 polypeptide.
2. The method of claim 1 , wherein the expression vector is a virus-based vector.
3. The method of claim 1 , wherein the nucleotide sequence encoding the EphB2 polypeptide is operably linked to a neuron-specific transcriptional control element, a microglia-specific transcriptional control element, an oligocyte-specific transcriptional control element, or an astroglia-specific transcriptional control element.
4. The method of claim 1 , wherein the EphB2 polypeptide comprises an amino acid sequence having at least about 85% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:2.
5. The method of claim 1 , wherein the EphB2 polypeptide comprises an amino acid sequence having at least about 95% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:2.
6. The method of claim 1 , wherein the amyloid-beta-associated neurodegenerative disease is Alzheimer's disease.
7. The method of claim 1 , wherein the individual is a human.
8. The method of claim 1 , wherein said administering is intracranial.
9. A method for increasing the level and/or function of an EphB2 polypeptide in a neuron, the method comprising introducing into the neuron a nucleic acid expression vector comprising a nucleotide sequence encoding an EphB2 polypeptide.
10. The method of claim 9 , wherein the neuron is a dentate gyrus granule cell.
11. The method of claim 9 , wherein the expression vector is a virus-based vector.
12. The method of claim 9 , wherein the nucleotide sequence encoding the EphB2 polypeptide is operably linked to a neuron-specific transcriptional control element, a microglia-specific transcriptional control element, or an astroglia-specific transcriptional control element.
13. The method of claim 9 , wherein the EphB2 polypeptide comprises an amino acid sequence having at least about 85% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:2.
14. The method of claim 9 , wherein the EphB2 polypeptide comprises an amino acid sequence having at least about 95% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:2.
15. The method of claim 9 , wherein increasing the function of the EphB2 increases NMDA receptor activity in the cell.
16. The method of claim 15 , wherein EphB2 increases NMDA receptor activity by phosphorylating the NDMA receptor.
17. The method of claim 15 , wherein EphB2 increases NMDA receptor activity in a tyrosine kinase-independent manner.
18. A method of identifying a candidate agent for the treatment of an amyloid-beta-induced neurodegenerative disease, the method comprising:
a) contacting an EphB2 polypeptide and an amyloid-beta polypeptide with a test agent; and
b) determining the effect, if any, of the test agent on binding of the amyloid-beta polypeptide to the EphB2 polypeptide,
wherein a test agent that reduces binding of the amyloid-beta polypeptide to the EphB2 polypeptide is a candidate agent for treating an amyloid-beta-induced neurodegenerative disease.
19. A method of identifying a candidate agent for the treatment of an amyloid-beta-induced neurodegenerative disease, the method comprising:
a) contacting a cell that expresses an EphB2 polypeptide with a test agent; and
b) determining the effect, if any, of the test agent on the level of the EphB2 in the cell, wherein a test agent that increases the level of the EphB2 polypeptide in the cell is a candidate agent for treating an amyloid-beta-induced neurodegenerative disease.
20. The method of claim 19 , wherein the cell is a neuron.
21. The method of claim 19 , wherein the EphB2 polypeptide comprises an amino acid sequence having at least about 85% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 2.
22. The method of claim 19 , wherein the EphB2 polypeptide comprises an amino acid sequence having at least about 95% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:2.
23. The method of claim 18 , wherein the EphB2 polypeptide comprises an amino acid sequence having at least about 85% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:2.
24. The method of claim 18 , wherein the EphB2 polypeptide comprises an amino acid sequence having at least about 95% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:2.
25. The method of claim 18 , wherein the amyloid-beta polypeptide comprises the amino acid sequence set forth in SEQ ID NO:5.
26. The method of claim 18 , wherein the amyloid-beta polypeptide comprises a moiety that provides for detection, purification, or immunoprecipitation.
27. The method of claim 18 , wherein EphB2 polypeptide comprises a moiety that provides for detection, purification, or immunoprecipitation.
28. The method of claim 1 , wherein said administering is systemic.
29. The method of claim 1 , wherein said expression vector is formulated with one or more agents that facilitate crossing the blood-brain barrier.