Method of inducing the formation of neurofibrillary tangles in transgenic animals

Abstract

The present invention discloses a method and an in-vivo assay system useful for the identification and testing of modulating agents as well as for the validation of therapies of neurodegenerative diseases associated with the formation of neurofibrillary tangles, in particular Alzheimer's disease. The present invention is based on the surprising finding that injection of β-amyloid Aβ 42 fibrils into brains of P301L mutant tau transgenic mice caused several-fold increases in the numbers and an accelerated production of neurofibrillary tangles in cell bodies predominantly within the amygdala. The induced neurofibrillary tangles occurred as early as 18 days after Aβ 42 injections and displayed striking features of neurofibrillary tangles of several human neurodegenerative diseases, particularly Alzheimer's disease.

1 . A method of increasing the number of neurofibrillary tangles in a non-human transgenic animal which expresses a recombinant gene coding for tau protein wherein the increase of neurofibrillary tangles is induced through admission of APP, or a fragment, or derivative, or variant thereof, in particular β-amyloid.  
     
     
         2 . A method of accelerating the production of neurofibrillary tangles in a non-human transgenic animal which expresses a recombinant gene coding for tau protein wherein the accelerated production of neurofibrillary tangles is induced through admission of APP, or a fragment, or derivative, or variant thereof, in particular β-amyloid.  
     
     
         3 . The method according to  claim 1  wherein said β-amyloid is Aβ 42 .  
     
     
         4 . The method according to  claim 3  wherein said Aβ 42  is fibrillar, pre-aggregated, or aggregated.  
     
     
         5 . The method according to  claim 1  wherein said transgenic animal is a mouse.  
     
     
         6 . The method according to  claim 5  wherein said mouse expresses a recombinant gene coding for human tau.  
     
     
         7 . The method according to  claim 5  wherein said mouse expresses a recombinant gene coding for P301L mutant tau.  
     
     
         8 . The method according to  claim 1  wherein β-amyloid is admitted through injection into the brain of said animal, in particular through injection into the hippocampus or the cortex.  
     
     
         9 . The method according to  claim 1  wherein β-amyloid or a fragment, or derivative, or variant of APP is admitted through co-expressing a recombinant gene coding for APP, said APP being enzymatically processed to generate β-amyloid or said fragment, or derivative, or variant of APP.  
     
     
         10 . The method according to  claim 9  wherein said APP is a mutant APP.  
     
     
         11 . The method according to  claim 1  wherein the increase of neurofibrillary tangles is predominantly in the amygdala of the animal's brain, in particular the basolateral amygdala.  
     
     
         12 . The method according to  claim 1  wherein the increase of neurofibrillary tangles is several-fold, preferably at least two-fold, as compared to a control animal to which no APP or a fragment, or derivative, or variant thereof, in particular β-amyloid, has been administered.  
     
     
         13 . The method according to  claim 1  wherein the increase of neurofibrillary tangles is at least five-fold as compared to a control animal to which no APP or a fragment, or derivative, or variant thereof, in particular β-amyloid, has been administered.  
     
     
         14 . The method according to  claim 1  for inducing neuropil threads and/or degeneration of neurites.  
     
     
         15 . A non-human transgenic animal which expresses a recombinant gene coding for tau protein wherein said animal is capable of producing neurofibrillary tangles.  
     
     
         16 . A non-human transgenic animal which expresses a recombinant gene coding for tau protein wherein said animal is capable of producing an increased number of neurofibrillary tangles.  
     
     
         17 . A non-human transgenic animal which expresses a recombinant gene coding for tau protein wherein said animal is capable of accelerated production of neurofibrillary tangles.  
     
     
         18 . The animal according to  claim 15  to  17  wherein neurofibrillary tangles are produced which are comparable to those commonly found in human neurodegenerative diseases.  
     
     
         19 . The animal of  claim 15  wherein said animal comprises APP or a fragment, or derivative, or variant thereof, in particular β-amyloid, in an amount sufficient to induce the production of neurofibrillary tangles.  
     
     
         20 . The animal according to  claim 16  wherein the increase of neurofibrillary tangles is induced through admission of APP, or a fragment, or derivative, or variant thereof, in particular β-amyloid.  
     
     
         21 . The animal according to  claim 15 , wherein β-amyloid is admitted through injection into the brain of said animal, in particular through injection into the hippocampus or the cortex.  
     
     
         22 . The animal according to  claim 15  wherein said animal co-expresses a recombinant gene coding for APP, or a fragment, or derivative, or variant thereof, said APP being enzymatically processed to generate a cleavage product, said cleavage product being preferably β-amyloid.  
     
     
         23 . The animal of  claim 22  wherein said APP is a mutant APP.  
     
     
         24 . Use of the animal according to  claim 15  as an in-vivo assay to determine or validate the efficacy of modulating agents, or therapies, in particular amyloid-lowering therapies or NFT-reducing therapies.  
     
     
         25 . The use according to  claim 24  wherein said modulating agents, or therapies are for neurodegenerative diseases, in particular Alzheimer's disease, frontotemporal dementia (FTD), and other neurodegenerative diseases accompanied by neurofibrillary tangle formation.