RbAp48 transgenic mice for drug discovery in age-related memory decline

Patent metadata

Field	Value
Publication number	US-9387263-B2
Application number	US-201214236945-A
Country	US
Kind code	B2
Filing date	Aug 2, 2012
Priority date	Aug 5, 2011
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

Abstract

Described is a transgenic mouse with two transgenes, each of which transgene comprises a DNA sequence encoding a dominant negative form of RbAp48 protein, wherein the expression of the dominant negative form of RbAp48 is spatially restricted to the forebrain by a CaM Kinase IIa promoter and wherein the expression of the dominant negative form of RbAp48 is controlled by tetracycline-controlled transcriptional activation. Also provided are methods for evaluating in the transgenic mouse the potential therapeutic effect of an agent for slowing, inhibiting or preventing age-related memory decline in a mammalian subject.

First claim

What is claimed is:

1. A transgenic mouse whose genome comprises:
i) a nucleic acid sequence encoding a dominant negative RbAp48 (RbAp48-DN) protein operably linked to a tetracycline promoter; and
ii) a nucleic acid sequence encoding a tetracycline controlled transactivator (tTA) operably linked to a CaM Kinase IIa promoter, wherein expression of the RbAp48-DN is restricted to the forebrain, and wherein said mouse is capable of having a memory deficit as compared to a wild-type mouse upon administration of tetracycline.

2. The transgenic mouse of claim 1 , wherein said RbAp48-DN lacks the N-terminal 54 amino acids of RbAp48.

3. A method for identifying an agent that slows, inhibits, or prevents a memory deficit, the method comprising:
a) administering tetracycline to the mouse of claim 1 such that expression of RbAp48-DN is induced in the brain and a memory deficit occurs;
b) administering an agent to the mouse of step a);
c) determining the memory of the mouse of step b), wherein increased memory as compared to a transgenic mouse of claim 1 not given the agent indicates the agent slows, inhibits, or prevents a memory deficit.

4. The method of claim 3 , wherein the agent increases RbAp48 expression.

5. The method of claim 3 , wherein the agent is epicatechin.

6. The method of claim 3 , wherein the agent is a histone acetyl transferase.

7. The method of claim 3 , wherein the agent is a histone deactylase (HDAC) inhibitor.

8. The method of claim 7 , wherein the HDAC inhibitor is selected from the group consisting of belinostat, mocetinostat, panobinostat, dacinostat, 4-Dimethylamino-N-(6-hydoxycarbamoylhexyl)-beinzamide, N-(2-aminophenyl)-N′-phenyl-octanediamide, etinostat, tacedinaline, suberoylanilide hydroxamic acid (SAHA), trichostatin A, traproxin B, valproic acid, (E)-3-(2-butyl-1-(2-(diethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide, romidepsin, givinostat, and sulforaphane.

9. The method of claim 3 , wherein the agent is a phosphodiesterase inhibitor.

10. The method of claim 9 , wherein the phosphodiesterase inhibitor is selected from the group consisting of vinpocetine, erythro-9-(2-hydroxy-3-nonyl)adenine), arofyllin, denbufylline, Drotaverine, etazolate, filaminast, (3R,5R)-5-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-(3-methylbenzyl)piperidin-2-one, ibudilast, irsogladine, mesembrine, roflumilast, rolipram, MEM 1917, MEM 1414.

11. The method of claim 3 , wherein the memory is assessed using novel object recognition.

12. The method of claim 3 , wherein the memory is assessed using the Morris water maze.

13. The method of claim 3 , wherein expression of RbAp48-DN is induced 10 days prior to administering the agent.

14. The method of claim 3 , further comprising determining the cerebral blood volume (cbv) in the dentate gyrus in the mouse of step b), wherein increased cbv as compared to a transgenic mouse of claim 1 not given the agent further indicates the agent slows, inhibits, or prevents a memory deficit.

Assignees

• Small Scott A
• Pavlopoulos Ilias
• Kandel Eric R
• Univ Columbia

Inventors

• Small Scott A
• Pavlopoulos Ilias
• Kandel Eric R

Classifications

• C07K14/47 Primary

  from mammals · CPC title

• A01K2227/105

  Murine · CPC title

• A01K2217/203

  Animal model comprising inducible/conditional expression system, e.g. hormones, tet · CPC title

• A61K38/45

  Transferases (2) · CPC title

• A01K2217/00

  Genetically modified animals · CPC title