Transgenic mice over-expressing receptor for advanced glycation endproduct (rage) in brain and uses thereof

Abstract

The present invention provides for a transgenic non-human animal whose cells contain a DNA sequence comprising: (a) a nerve tissue specific promoter; and (b) a DNA sequence which encodes a receptor for advanced glycation endproducts (RAGE), wherein the promoter and the DNA sequence which encodes the receptor for advanced glycation endproducts (RAGE) are operatively linked to each other and integrated in the genome of the non-human animal, and wherein said non-human animal exhibits a reduced amount of cerebral tissue infarcted following a transient middle cerebral artery occlusion compared to an identical non-human animal lacking said DNA sequence.

1 . A transgenic non-human animal whose cells contain a DNA sequence comprising:
 (a) a nerve tissue specific promoter; and   (b) a DNA sequence which encodes a receptor for advanced glycation endproducts (RAGE),   wherein the promoter and the DNA sequence which encodes the receptor for advanced glycation endproducts (RAGE) are operatively linked to each other and integrated in the genome of the non-human animal, and   wherein said non-human animal exhibits a reduced amount of cerebral tissue infarcted following a transient middle cerebral artery occlusion compared to an identical non-human animal lacking said DNA sequence.   
     
     
         2 . The transgenic non-human animal of  claim 1 , wherein the promoter is platelet derived growth factor (PDGF)-B-chain promoter. 
     
     
         3 . The transgenic non-human animal of  claim 1 , wherein the DNA sequence which encodes amyloid-beta peptide alcohol dehydrogenase is a human DNA sequence. 
     
     
         4 . The transgenic non-human animal of  claim 1 , wherein the reduction of infarcted cerebral tissue is about a 50% reduction. 
     
     
         5 . The transgenic non-human animal of  claim 1 , wherein the transgenic non-human animal is a mouse, a rat, a sheep, a dog, a primate, or a reptile. 
     
     
         6 . The transgenic non-human animal of  claim 1 , wherein the non-human animal is a mammal. 
     
     
         7 . A method for evaluating in a non-human transgenic animal the potential therapeutic effect of an agent for treating Alzheimer's disease in a human, which comprises:
 (a) administering an agent to a transgenic non-human animal whose cells comprise a nerve tissue specific promoter operatively linked to a DNA sequence which encodes receptor for advanced glycation endproducts (RAGE); and   (b) determining the therapeutic effect of the agent on the transgenic non-human animal by monitoring basal synaptic transmission or synaptic plasticity, wherein an increase in basal synaptic transmission or synaptic plasticity indicates that the agent would have a potential therapeutic effect on Alzheimer's disease in a human.   
     
     
         8 . The method of  claim 7 , wherein the promoter is platelet derived growth factor (PDGF)-B-chain promoter. 
     
     
         9 . The method of  claim 7 , wherein the non-human animal is a mouse, a rat, a sheep, a dog, a primate, or a reptile. 
     
     
         10 . The method of  claim 7 , wherein the non-human animal is a mammal. 
     
     
         11 . A method for identifying whether an agent or a compound is an inhibitor of receptor for advanced glycation endproduct (RAGE) in vivo, which comprises:
 (a) obtaining a non-human transgenic animal whose cells overexpress RAGE in neurons;   (b) administering an agent or compound to the transgenic non-human animal; and   (c) determining whether the transgenic non-human animal from step (b) exhibits a change in neuronal function from an identical transgenic non-human animal which was not administered the agent or compound;   wherein a determination of change in neuronal function indicates that the agent or compound is an inhibitor of RAGE in vivo.