Transgenic animal model of neurodegenerative disorders

Abstract

The present invention provides a transgenic animal model of Alzheimer's Disease designated TgCRND8 as well as a method for making such model, which allows for the characterization of the etiology of the disease as well as for provide a system for the development and testing of potential treatments.

1 . A transgenic non-human mammal whose genome comprises a transgene comprising a nucleotide sequence operably linked to a promoter and encoding a heterologous amyloid precursor protein 695 (APP 695 ) polypeptide wherein the lysine residue at position 670 is substituted by asparagine, the methionine residue at position 671 is substituted by leucine and the valine residue at position 717 is substituted by phenylalanine and wherein the transgene is expressed. 
     
     
         2 . The transgenic mammal of  claim 1  wherein the mammal is a mouse. 
     
     
         3 . The transgenic mouse of  claim 2  wherein the mouse is a (C3H×C57 BL6)×C57 mouse. 
     
     
         4 . The transgenic mouse of  claim 3  wherein the heterologous APP 695  is human APP 695 . 
     
     
         5 . The transgenic mouse of  claim 4  wherein the mouse displays abnormal Aβ deposition in its central nervous system. 
     
     
         6 . The transgenic mouse of  claim 4  wherein the animal displays an accelerated appearance of Alzheimer's Disease-related pathology. 
     
     
         7 . A transgenic mouse having the transgenic mouse of  claim 4  as an ancestor. 
     
     
         8 - 19 . (canceled) 
     
     
         20 . A method for screening a candidate compound for its efficacy in preventing or delaying the development of AD, the method comprising the steps of:
 (a) administering the candidate compound to a first transgenic mouse in accordance with  claim 2  prior to the appearance of a selected AD-related phenotypic trait in said mouse; and   (b) comparing the age at which said selected AD-related phenotypic trait appears in said mouse with the age at which said trait appears in a second transgenic mouse of the same type to which the compound had not been administered;   wherein an increased age of appearance of the trait in the first mouse compared to that in the second mouse indicates efficacy of the compound.   
     
     
         21 . The method of  claim 20  wherein the trait is a behavioural deficit. 
     
     
         22 . The method of  claim 20  wherein the trait is abnormal CNS amyloid deposition. 
     
     
         23 . A method for screening a candidate compound for its efficacy in ameliorating the symptoms of Alzheimer's Disease, the method comprising the steps of:
 (a) administering the candidate compound to a first transgenic mouse in accordance with  claim 2 ;   (b) determining the performance of said mouse in a memory or learning test; and   (c) comparing the performance of said mouse with the performance of a second transgenic mouse of the same type to which the compound has not been administered;   wherein an improved performance of the first mouse compared to that of the second mouse indicates efficacy of the compound.   
     
     
         24 . A method of producing a transgenic non-human mammal that displays abnormal Aβ deposition in its central nervous system comprising:
 (a) introducing into a fertilized oocyte of said mammal a transgene comprising a nucleotide sequence operably linked to a promoter and encoding a heterologous amyloid precursor protein 695 (APP 695 ) polypeptide wherein the lysine residue at position 670 is substituted by asparagine, the methionine residue at position 671 is substituted by leucine and the valine residue at position 717 is substituted by phenylalanine; 
 (b) transplanting said fertilized oocyte into a pseudopregnant mammal; 
 (c) allowing said fertilized oocyte to develop into a live born offspring; and 
 (d) selecting an offspring where genome comprises a transgene comprising a nucleotide sequence operably linked to a promoter and encoding a heterologous amyloid precursor protein 695 (APP 695 ) polypeptide wherein the lysine residue at position 670 is substituted by asparagine, the methionine residue at position 671 is substituted by leucine and the valine residue at position 717 is substituted by phenylalanine and wherein the transgene is expressed. 
 
     
     
         25 . The method of  claim 24  wherein the mammal is a mouse. 
     
     
         26 . The method of  claim 24  wherein the promoter is the prion protein cos.Tet promoter. 
     
     
         27 . A nucleotide sequence encoding a heterologous amyloid precursor protein 695 (APP 695 ) polypeptide wherein the lysine residue at position 670 is substituted by asparagine, the methionine residue at position 671 is substituted by leucine and the valine residue at position 717 is substituted by phenylalanine. 
     
     
         28 . A vector comprising the nucleotide sequence of  claim 27  operably linked to a promoter. 
     
     
         29 . A method of reducing a cognitive deficit in a mammal which suffers from abnormal amyloid deposition in its central nervous system, the method comprising administering to the mammal an amount of an Aβ peptide effective to reduce the cognitive defect. 
     
     
         30 . The method of  claim 29  wherein the abnormal amyloid deposition is Aβ deposition. 
     
     
         31 . The method of  claim 29  wherein the administered peptide is Aβ42. 
     
     
         32 . The method of  claim 29  wherein the mammal is a human suffering from Alzheimer's Disease. 
     
     
         33 . Use of an Aβ peptide to manufacture a medicament for reducing a cognitive deficit in a mammal which suffers from abnormal amyloid deposition in its nervous system. 
     
     
         34 . The use of  claim 33  wherein the Aβ peptide is Aβ42. 
     
     
         35 . The use of  claim 33  wherein the medicament is for the prevention or treatment of Alzheimer's Disease.