Alzheimer's related proteins and methods of use

Abstract

Disclosed is a method for identifying substances that alter the interaction of a presenilin protein with a presenilin-binding protein, including contacting at least the interacting domain of a presenilin protein to a presenilin-binding protein in the presence of a test substance, and measuring the interaction of the presenilin protein and the presenilin-binding protein. Also disclosed is method for identifying substances that modulate the nuclear translocation of an armadillo protein, including providing a culture of cells that express the armadillo protein and a mutant presenilin protein, or a functional fragment thereof that binds an armadillo protein; contacting the culture with a test substance; inducing nuclear translocation of the armadillo protein in the cells; and measuring levels of nuclear armadillo protein as compared to a control as an indication of modulatory activity of the test substance. Further disclosed is method for screening individuals for presenilin alleles associated with Alzheimer's Disease or related disorders, including obtaining cells from an individual to be tested for Alzheimer's Disease or a related disorder; inducing nuclear translocation of an armadillo protein in the cells; and measuring levels of the nuclear armadillo protein as compared to a control as an indication of the presence or absence of presenilin alleles associated with Alzheimer's Disease or a related disorder.

1 . A method for identifying substances that alter the interaction of a presenilin protein with a presenilin-binding protein, comprising:
 (a) contacting at least the interacting domain of a presenilin protein to a presenilin-binding protein in the presence of a test substance, and   (b) measuring the interaction of the presenilin protein and the presenilin-binding protein.   
     
     
         2 . The method of  claim 1 , wherein said interacting domain is mutated relative to the interacting domain of a normal PS1 protein. 
     
     
         3 . The method of  claim 1 , wherein said interacting domain comprises amino acid residues from about 260 to about 409 of a mutant PS1 protein. 
     
     
         4 . The method of  claim 1 , wherein said interacting domain comprises amino acid residues from about 372 to about 399 of a mutant PS1 protein. 
     
     
         5 . The method of  claim 1 , wherein said interacting domain comprises amino acid residues from about 266 to about 390 of a mutant PS2 protein. 
     
     
         6 . The method of  claim 1 , wherein said interacting domain comprises amino acid residues from about 350 to about 380 of a mutant PS2 protein. 
     
     
         7 . A method for identifying substances that modulate the nuclear translocation of an armadillo protein, comprising:
 (a) providing a culture of cells that express said armadillo protein and a mutant presenilin protein, or a functional fragment thereof that binds said armadillo protein;   (b) contacting said culture with a test substance;   (c) inducing nuclear translocation of said armadillo protein in said cells; and   (d) measuring levels of nuclear armadillo protein as compared to a control as an indication of modulatory activity of said test substance.   
     
     
         8 . The method of  claim 7 , wherein said armadillo protein is β-catenin. 
     
     
         9 . The method of  claim 7 , wherein said armadillo protein is hNPRAP. 
     
     
         10 . The method of  claim 7 , wherein said armadillo protein is p0071. 
     
     
         11 . The method of  claim 7 , wherein (c) comprises culturing said cells in the presence of a lithium salt. 
     
     
         12 . The method of  claim 7 , wherein said mutant presenilin protein comprises amino acid residues from about 260 to about 409 of a mutant PS1 protein. 
     
     
         13 . The method of  claim 7 , wherein said mutant presenilin protein comprises amino acid residues from about 372 to about 399 of a mutant PS1 protein. 
     
     
         14 . The method of  claim 7 , wherein said mutant presenilin protein comprises amino acid residues from about 266 to about 390 of a mutant PS2 protein. 
     
     
         15 . The method of  claim 7 , wherein said mutant presenilin protein comprises amino acid residues from about 350 to about 380 of a mutant PS2 protein. 
     
     
         16 . The method of  claim 7 , wherein said cells are selected from the group consisting of fibroblasts, leukocytes, neuronal cells, human embryonic kidney cells and  D. melanogaster  cells. 
     
     
         17 . The method of  claim 7 , wherein said control comprises cells expressing a wild-type presenilin and said armadillo protein. 
     
     
         18 . A method for screening individuals for presenilin alleles associated with Alzheimer's Disease or related disorders, comprising:
 (a) obtaining cells from an individual to be tested for Alzheimer's Disease or a related disorder;   (b) inducing nuclear translocation of an armadillo protein in said cells; and   (c) measuring levels of said nuclear armadillo protein as compared to a control as an indication of the presence or absence of presenilin alleles associated with Alzheimer's Disease or a related disorder.   
     
     
         19 . The method of  claim 18 , wherein (b) comprises culturing said cells in the presence of a lithium salt. 
     
     
         20 . The method of  claim 18 , wherein said control comprises cells that express normal presenilin and said armadillo protein. 
     
     
         21 . The method of  claim 18 , wherein said armadillo protein is β-catenin. 
     
     
         22 . The method of  claim 18 , wherein said armadillo protein is hNPRAP. 
     
     
         23 . The method of  claim 18 , wherein said armadillo protein is p0071.