Transgenic Animal Expressing Alzheimer's Tau Protein

Abstract

The present invention provides transgenic non-human animals and non-human mammalian somatic and germ cells harbouring a human DNA sequence encoding Alzheimer's Disease (AD) derived tau protein, capable of inducing AD pathology in transgenic animals. Alzheimer's tau protein is expressed on specific genetic backgrounds allowing also simulation of different human diseases including hypertension, diabetes, hyper-cholesterolemia, which are associated with neurodegeneration and are considerable risk factors for AD development. Transgenic animals and cells of the present invention exhibit neurofibrillary pathology and may serve as in vivo and also in vitro assay systems for screening and developing therapeutic and preventive substances and also diagnostic markers and probes for tauopathies and AD. Furthermore these transgenic animals and cell lines derived thereof provide an in vivo and in vitro assay system for neurodegenerative disorders preferably tauopathies and AD which are the result of combinations with other disease as hypertension and others representing risk factors associated with the process of neurodegeneration.

1 - 56 . (canceled) 
     
     
         57 . A transgenic mouse having germ and somatic cells whose genome comprises a transgene comprising a DNA construct comprising:
 (i) a cDNA molecule coding for a transgenic truncated tau protein, wherein:
 the cDNA molecule is truncated relative to a cDNA encoding full-length 4-repeat or 3-repeat human tau protein both at a 5′- or N-terminal truncation site and at a 3′- or C-terminal truncation site, wherein the 5′- or N-terminal truncation site is located at least 30 nucleotides downstream of the start codon and the 3′- or C-terminal truncation site is located at least 30 nucleotides upstream of the stop codon of the full length human tau cDNA sequence coding for either a 4-repeat or a 3-repeat tau protein; and 
 the cDNA molecule comprises SEQ ID No. 9; and 
   (ii) a tissue-specific promoter, wherein the cDNA molecule is operably linked to the tissue-specific promoter, wherein the tissue-specific promoter is functional in mouse brain cells;
 the transgenic truncated tau protein so encoded is truncated at both the N-terminus and at the C-terminus, relative to full-length human tau, and is expressed in the brain of the transgenic mouse; and 
 neurofibrillary (NF) pathology associated with Alzheimer's disease occurs in the resulting transgenic mouse expressing the transgenic truncated tau protein in the brain when compared to non-transgenic mouse counterparts. 
   
     
     
         58 . A method of screening for a substance potentially useful in treating Alzheimer's disease, the method comprising:
 (i) administering the substance to one or more transgenic mice of  claim 57 ;   (ii) detecting at least one change of in neurofibrillary pathology in a transgenic mouse of (i) relative to the neurofibrillary pathology of counterpart mice of  claim 57  to which the substance was not administered;
 wherein the at least one change in neurofibrillary pathology comprises a reduction in at least one of the following: (a) the number of neurofibrillary tangles, (b) the number of ghost tangles, (c) the number of neuropil threads, or (d) the combination thereof; 
   wherein the detected reduction indicates that the substance is potentially useful in treating Alzheimer's Disease.   
     
     
         59 . A transgenic mouse having germ and somatic cells whose genome comprises a transgene comprising a DNA construct comprising:
 (i) a cDNA molecule coding for the transgenic truncated tau protein encoded by SEQ ID No. 3, wherein the cDNA molecule comprises SEQ ID NO. 9; and   (ii) a promoter, wherein the cDNA molecule is operably linked to the promoter, and wherein the promoter is a Thy-1 promoter; and   
       wherein the transgenic truncated tau protein so encoded is truncated at both the N-terminus and at the C-terminus, relative to full-length human tau protein, and is expressed in the brain of the transgenic mouse; and 
       wherein neurofibrillary (NF) pathology associated with Alzheimer's disease occurs in the resulting transgenic mouse expressing the transgenic truncated tau protein in the brain, when compared to non-transgenic mouse counterparts. 
     
     
         60 . A method of screening for a substance potentially useful in treating Alzheimer's disease, the method comprising:
 (i) administering the substance to one or more transgenic mice of  claim 59 ;   (ii) detecting at least one change in neurofibrillary pathology in a transgenic mouse of (i) relative to the neurofibrillary pathology of counterpart mice of  claim 59  to which the substance was not administered;
 wherein the at least one change in neurofibrillary pathology comprises a reduction in at least one of the following: (a) the number of neurofibrillary tangles, (b) the number of ghost tangles, (c) the number of neuropil threads, or (d) the combination thereof; 
   wherein the detected reduction indicates that the substance is potentially useful in treating Alzheimer's Disease.   
     
     
         61 . A transgenic mouse having germ and somatic cells whose genome comprises a transgene comprising a DNA construct comprising:
 (i) a cDNA molecule coding for the transgenic truncated tau protein encoded by SEQ ID No. 12, wherein the cDNA molecule comprises SEQ ID NO. 9; and   (ii) a promoter, wherein the cDNA molecule is operably linked to the promoter, and wherein the promoter is a Thy-1 promoter; and   
       wherein the transgenic truncated tau protein so encoded is truncated at both the N-terminus and at the C-terminus, relative to full-length human tau protein, and is expressed in the brain of the transgenic mouse; and 
       wherein neurofibrillary (NF) pathology associated with Alzheimer's disease occurs in the resulting transgenic mouse expressing the transgenic truncated tau protein in the brain, when compared to non-transgenic mouse counterparts. 
     
     
         62 . A method of screening for a substance potentially useful in treating Alzheimer's disease, the method comprising:
 (i) administering the substance to one or more transgenic mice of  claim 61 ;   (ii) detecting at least one change in neurofibrillary pathology in a transgenic mouse of (i) relative to the neurofibrillary pathology of counterpart mice of  claim 61  to which the substance was not administered;
 wherein the at least one change in neurofibrillary pathology comprises a reduction in at least one of the following: (a) the number of neurofibrillary tangles, (b) the number of ghost tangles, (c) the number of neuropil threads, or (d) the combination thereof; 
   wherein the detected reduction indicates that the substance is potentially useful in treating Alzheimer's Disease.   
     
     
         63 . A transgenic mouse having germ and somatic cells whose genome comprises a transgene comprising a DNA construct comprising:
 (i) a cDNA molecule coding for the transgenic truncated tau protein encoded by SEQ ID No. 3, wherein the cDNA molecule comprises SEQ ID NO. 9; and   (ii) a tissue-specific promoter, wherein the cDNA molecule is operably linked to the tissue-specific promoter, wherein the tissue-specific promoter is functional in mouse brain cells; and   
       wherein the transgenic truncated tau protein so encoded is truncated at both the N-terminus and at the C-terminus, relative to full-length human tau protein, and is expressed in the brain of the transgenic mouse; and 
       wherein neurofibrillary (NF) pathology associated with Alzheimer's disease occurs in the resulting transgenic mouse expressing the transgenic truncated tau protein in the brain, when compared to non-transgenic mouse counterparts. 
     
     
         64 . A method of screening for a substance potentially useful in treating Alzheimer's disease, the method comprising:
 (i) administering the substance to one or more transgenic mice of  claim 63 ;   (ii) detecting at least one change in neurofibrillary pathology in a transgenic mouse of (i) relative to the neurofibrillary pathology of counterpart mice of  claim 63  to which the substance was not administered;   wherein the at least one change in neurofibrillary pathology comprises a reduction in at least one of the following: (a) the number of neurofibrillary tangles, (b) the number of ghost tangles, (c) the number of neuropil threads, or (d) the combination thereof;   wherein the detected reduction indicates that the substance is potentially useful in treating Alzheimer's Disease.   
     
     
         65 . A transgenic mouse having germ and somatic cells whose genome comprises a transgene comprising a DNA construct comprising:
 (i) a cDNA molecule coding for the transgenic truncated tau protein encoded by SEQ ID No. 12, wherein the cDNA molecule comprises SEQ ID NO. 9; and   (ii) a tissue-specific promoter, wherein the cDNA molecule is operably linked to the tissue-specific promoter, wherein the tissue-specific promoter is functional in mouse brain cells; and   
       wherein the transgenic truncated tau protein so encoded is truncated at both the N-terminus and at the C-terminus, relative to full-length human tau protein, and is expressed in the brain of the transgenic mouse; and 
       wherein neurofibrillary (NF) pathology associated with Alzheimer's disease occurs in the resulting transgenic mouse expressing the transgenic truncated tau protein in the brain, when compared to non-transgenic mouse counterparts. 
     
     
         66 . A method of screening for a substance potentially useful in treating Alzheimer's disease, the method comprising:
 (i) administering the substance to one or more transgenic mice of  claim 65 ;   (ii) detecting at least one change in neurofibrillary pathology in a transgenic mouse of (i) relative to the neurofibrillary pathology of counterpart mice of  claim 65  to which the substance was not administered;
 wherein the at least one change in neurofibrillary pathology comprises a reduction in at least one of the following: (a) the number of neurofibrillary tangles, (b) the number of ghost tangles, (c) the number of neuropil threads, or (d) the combination thereof; 
   wherein the detected reduction indicates that the substance is potentially useful in treating Alzheimer's Disease.