Transgenic animal model for alzheimer disease

Abstract

Animal model involving transgenic manipulation of amyloid precursor protein, useful for testing potential therapeutic agents for the treatment of neurodegenerative disorders, in particular Alzheimer's disease.

1 . A recombinant DNA construct comprising a polynucleotide encoding a human APP polypeptide comprising the Swedish mutation, functionally linked to a Thy-1 promoter element, provided that the Thy-1 promoter element is a rodent, e.g. mouse, Thy-1 promoter element when the Swedish mutation is the only mutation present in the APP polypeptide.  
     
     
         2 . A recombinant DNA construct according to  claim 1 , in which the APP polypeptide additionally comprises the London mutation.  
     
     
         3 . A recombinant DNA construct according to  claim 1  or  2 , in which the Thy-1 promoter element is a human Thy-1 promoter element.  
     
     
         4 . A transgenic non-human animal which exhibits both APP and tau-linked features of AD pathology, and preferably also behavioural changes of AD, and transgenic cells thereof.  
     
     
         5 . A transgenic non-human animal cell, wherein DNA encoding a mutant human APP comprising only one mutation is expressed at such a level that the amount of transgene mRNA exceeds the endogenous message by about 5 times or more.  
     
     
         6 . A transgenic non-human animal cell according to  claim 5  in which the only one mutation is the Swedish mutation.  
     
     
         7 . A transgenic non-human animal cell, wherein DNA encoding a mutant human APP comprising two mutations is expressed at such a level that the amount of transgene mRNA exceeds the endogenous message by about 2 times  
     
     
         8 . A transgenic non-human animal cell according to  claim 7  in which the two mutations are the Swedish mutation and the London mutation.  
     
     
         9 . A transgenic non-human animal cell, wherein DNA encoding a mutant human APP comprising the three or more mutations is expressed at such a level that the amount of transgene mRNA exceeds the endogenous message by 2 times or less.  
     
     
         10 . A transgenic non-human animal cell, wherein DNA encoding a human APP polypeptide comprising the Swedish mutation is expressed under the transcriptional control of a Thy-1 promoter element, provided that when Swedish mutation is the only mutation present in the APP polypeptides the Thy-1 promoter element is a rodent, e.g. mouse, Thy-1 promoter element.  
     
     
         11 . A transgenic non-human animal cell according to  claim 10 , in which the human APP polypeptide additionally comprises the London mutation.  
     
     
         12 . A transgenic non-human animal cell according to  claim 11 , wherein the Thy-1 promoter element is a human Thy-1 promoter element.  
     
     
         13 . A transgenic non-human animal, in the cells of which DNA encoding a human APP having only one mutation is expressed at such a level that the amount of transgene mRNA exceeds the endogenous message by about 5 times or more.  
     
     
         14 . A transgenic non-human animal according to  claim 13 , in which the only one mutation is the Swedish mutation.  
     
     
         15 . A transgenic non-human animal, in the cells of which DNA encoding a human APP having two mutations is expressed at such a level that the amount of transgene mRNA exceeds the endogenous message by about 2 times.  
     
     
         16 . A transgenic non-human animal according to  claim 15 , in which the two mutations are the Swedish mutation and the London mutation.  
     
     
         17 . A transgenic non-human animal, in the cells of which DNA encoding a human APP polypeptide comprising the Swedish mutation is expressed under the transcriptional control of a Thy-1 promoter element, provided that when the Swedish mutation is the only mutation present in the APP polypeptide the Thy-1 promoter element is a rodent, e.g. mouse, Thy-1 promoter element.  
     
     
         18 . A transgenic non-human animal according to  claim 17  in which the APP polypeptide additionally comprises the London mutation.  
     
     
         19 . A transgenic non-human animal according to  claim 13  to  18 , which is a mouse.  
     
     
         20 . A method of producing a transgenic non-human animal, wherein said animal is generated by incorporating a recombinant DNA construct according to  claim 1  into its genome.  
     
     
         21 . A method of producing transgenic non-human animals capable of developing a neurodegenerative disease pathology, comprising injection of transcription units obtained from a recombinant DNA construct according to  claim 1  into pronuclei of non-human animal embryos and breeding the so obtained founder animals.  
     
     
         22 . A method for testing a potential therapeutic agent for a specified condition, wherein a transgenic animal according to any one of  claims 13  to  19  is used or a cell according to  claim 5  to  12  is used as target cell.  
     
     
         23 . A method according to  claim 22 , wherein the agent is administered to a transgenic non-human animal produced according to the method of  claim 20  or  21 .  
     
     
         24 . A method according to  claim 22 , wherein the condition is a neurodegenerative disease.  
     
     
         25 . A method according to  claim 22 , wherein the condition is Alzheimer's disease.  
     
     
         26 . A screening or characterization assay consisting in or including a method according to any one of  claims 23  to  25 .  
     
     
         27 . A screening assay kit comprising cells according to any one of  claims 5  to  12 .  
     
     
         28 . A compound for use in the treatment of a neurodegenerative disease, which has been identified using an assay or assay kit according to  claim 26  or  27 .