Transgenic mice comprising a genomic human tau transgene

Abstract

The invention provides transgenic mice comprising tau transgenes, and methods of preparing and using the transgenic mice. For example, the invention provides a transgenic mouse, the genome of the cells of which stably comprise a DNA molecule which comprises a human genomic DNA sequence comprising a human tau promoter and which DNA sequence encodes human tau.

1 . A transgenic mouse, the genome of the cells of which stably comprise a DNA molecule which comprises a human genomic DNA sequence comprising a human tau promoter and which DNA sequence encodes human tau, wherein the DNA sequence is expressed in the transgenic mouse so as to result in the transgenic mouse expressing six isoforms of human tau, wherein the transgenic mouse does not express endogenous murine tau, wherein the DNA sequence comprises one SrfI restriction site in the human tau coding region, and wherein the transgenic mouse accumulates filamentous tau in dendrites of hippocampal neurons.  
     
     
         2 . The transgenic mouse of  claim 1  which develops abnormal spinal cord pathology.  
     
     
         3 . The transgenic mouse of  claim 1  which has motor abnormalities.  
     
     
         4 . The transgenic mouse of  claim 1  wherein the human genomic DNA sequence comprises at least one alteration.  
     
     
         5 . The transgenic mouse of  claim 4  wherein the alteration comprises at least one mutation.  
     
     
         6 . The transgenic mouse of  claim 4  wherein the alteration comprises at least one insertion or at least one deletion.  
     
     
         7 . The transgenic mouse of  claim 1  which has a dementing disorder or a neurodegenerative disorder.  
     
     
         8 . A transgenic mouse, the genome of the cells of which stably comprise a DNA molecule which comprises a human genomic DNA sequence comprising a human tau promoter and which DNA sequence encodes human tau, wherein the DNA sequence is expressed in the transgenic mouse so as to result in the transgenic mouse expressing six isoforms of human tau, wherein the DNA sequence comprises one SrfI restriction site in the human tau coding region, and wherein the ratio of the six isoforms is altered in the transgenic mouse relative to the ratio in humans.  
     
     
         9 . Progeny of the transgenic mouse of  claim 1  or  8 .  
     
     
         10 . A method for expression of human tau in a mouse, comprising preparing the transgenic mouse of  claim 1  or  8 .  
     
     
         11 . The method of  claim 10  wherein the human genomic DNA sequence comprises at least one alteration.  
     
     
         12 . The method of  claim 10  wherein the alteration comprises at least one insertion or at least one deletion.  
     
     
         13 . The method of  claim 10  wherein the alteration is associated with a dementing disorder.  
     
     
         14 . The method of  claim 10  wherein the alteration is associated a neurodegenerative disorder.  
     
     
         15 . A method of using a transgenic mouse which expresses human tau to screen for an agent that reduces or inhibits a neurodegenerative disorder, comprising: 
 (a) administering the agent to the transgenic mouse of  claim 1;  and    (b) determining whether the agent reduces or inhibits a neurodegenerative disorder in the transgenic mouse relative to a transgenic mouse of  claim 1  which has not been administered the agent.    
     
     
         16 . A method to screen for an agent that reduces or inhibits abnormal tau formation, comprising: 
 (a) administering the agent to an organotypic slice culture comprising cells obtained from the brain of the transgenic mouse of  claim 1;  and    (b) determining whether the agent reduces or inhibits abnormal tau formation in the organotypic slice culture relative to an organotypic slice culture which has not been administered the agent or a corresponding organotypic slice culture comprising cells obtained from the brain of the transgenic mouse of  claim 8.