Genetic alterations related to familial alzheimer's disease

Abstract

Isolated nucleic acid molecules are provided encoding human PS1 gene products. Mutant PS1 polypeptides are also provided, as are vectors, host cells and recombinant methods for producing the same. The invention further relates to screening methods for identifying agonists and antagonists of the activity of the PS1 polypeptide and mutants thereof. Also provided are diagnostic methods for detecting Alzheimer's disease and therapeutic methods for treating the same.

What is claimed is:  
     
         1 . An isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence selected from the group consisting of: 
 (a) a nucleotide sequence encoding a mutant of the PS1 polypeptide having the complete amino acid sequence in FIG. 1 (SEQ ID NO:2);    (b) a nucleotide sequence encoding a mutant of the mature PS1 polypeptide having the amino acid sequence at positions 83-549 in FIG. 1 (SEQ ID NO:2); and    (c) a nucleotide sequence complementary to any of the nucleotide sequences in (a) or (b).    
     
     
         2 . The nucleic acid molecule of    claim 1    wherein said polynucleotide has the complete nucleotide sequence in FIG. 2 (SEQ ID NO:3).  
     
     
         3 . The nucleic acid molecule of    claim 1    wherein said polynucleotide has the nucleotide sequence in FIG. 2 (SEQ ID NO:3) encoding the mutant PS1 polypeptide having the complete amino acid sequence in FIG. 2 (SEQ ID NO:4).  
     
     
         4 . The nucleic acid molecule of    claim 1    wherein said polynucleotide has the nucleotide sequence in FIG. 2 (SEQ ID NO:3) encoding the mutant of the mature PS1 polypeptide having the amino acid sequence at positions 83-549 in FIG. 2 (SEQ ID NO:4).  
     
     
         5 . An isolated nucleic acid molecule comprising a polynucleotide which hybridizes under stringent hybridization conditions to a polynucleotide having a nucleotide sequence identical to a nucleotide sequence in (a), (b) or (c) of    claim 1   .  
     
     
         6 . An isolated nucleic acid molecule comprising a polynucleotide which encodes the amino acid sequence of an epitope-bearing portion of a mutant PS1 polypeptide having an amino acid sequence in (a) or (b) of    claim 1   .  
     
     
         7 . A method for making a recombinant vector comprising inserting an isolated nucleic acid molecule of    claim 1    into a vector.  
     
     
         8 . A recombinant vector produced by the method of    claim 11   .  
     
     
         9 . A method of making a recombinant host cell comprising introducing the recombinant vector of    claim 8    into a host cell.  
     
     
         10 . A recombinant host cell produced by the method of    claim 13   .  
     
     
         11 . A recombinant method for producing a mutant PS1 polypeptide, comprising culturing the recombinant host cell of    claim 10    under conditions such that said polypeptide is expressed and recovering said polypeptide.  
     
     
         12 . An isolated mutant presenilin 1 (PS1) polypeptide comprising an amino acid sequence selected from the group consisting of: 
 (a) the amino acid sequence shown in SEQ ID NO:4;    (b) the amino acid sequence shown in SEQ ID NO:28;    (c) the amino acid sequence shown in SEQ ID NO:30;    (d) the amino acid sequence shown in SEQ ID NO:32; and    (e) the amino acid sequence of an epitope-bearing portion of any one of the polypeptides of (a)-(d).    
     
     
         13 . An isolated antibody that binds specifically to a mutant PS1 polypeptide of    claim 12   .  
     
     
         14 . A method for diagnosing a patient having an increased likelihood of contracting Alzheimer's disease, comprising the steps of: 
 a) obtaining from a patient a biological sample containing nucleic acid;    b) incubating said nucleic acid with a probe which is capable of specifically hybridizing to a mutant PS1 gene under conditions and for time sufficient to allow hybridization to occur; and    c) detecting the presence of hybridized probe, and thereby determining that said patient has an increased likelihood of contracting Alzheimer's disease.    
     
     
         15 . A method for diagnosing a patient having an increased likelihood of contracting Alzheimer's disease, comprising the steps of: 
 a) contacting a biological sample obtained from a patient with an antibody as claimed in    claim 13    under conditions and for a time sufficient to allow binding of the antibody to the protein; and    b) detecting the presence of the bound antibody.