Signaling intermediates in an in vitro model of alzheimer's disease

Abstract

The invention provides a novel human protein, FISH adaptor protein, involved in amyloid β-protein-mediated cell death. Also provided are methods for modulating amyloid β-protein-mediated cell death using agents that interfere with the activity of FISH adaptor protein.

1 . A method of identifying an agent that modulates Aβ-induced cell death comprising contacting Aβ-treated neuronal cells with a candidate agent and detecting the survival rate of cells in the presence of the agent relative to the survival rate in the absence of the agent. 
     
     
         2 . The method of  claim 1 , wherein modulation comprises inhibition of an Aβ activity. 
     
     
         3 . The method of  claim 2 , wherein the Aβ activity is chosen from one or more of phosphorylation of a FISH adapter protein, interaction of a FISH adapter protein with an ADAM protein, and cleavage of an ADAM protein. 
     
     
         4 . The method of  claim 3 , wherein the FISH adapter protein is phosphorylated on one or more tyrosine residues. 
     
     
         5 . The method of  claim 3 , wherein the ADAM protein is ADAM12. 
     
     
         6 . The method of  claim 1 , wherein the cells are treated with Aβ either simultaneously or sequentially with the agent. 
     
     
         7 . The method of  claim 1 , wherein the agent is a peptide, a polypeptide, an antibody, a chemical compound, or a small molecule. 
     
     
         8 . The method of  claim 7 , wherein the antibody is monoclonal antibody. 
     
     
         9 . The method of  claim 7 , wherein the antibody is a polyclonal antibody. 
     
     
         10 . The method of  claim 8 , wherein the antibody is an anti-FISH antibody. 
     
     
         11 . The method of  claim 8 , wherein the antibody is an anti ADAM12 antibody. 
     
     
         12 . The method of  claim 7 , wherein the polypeptide is a mutant form of ADAM12. 
     
     
         13 . The method of  claim 12 , wherein the mutant form of ADAM12 comprises a deletion in the metalloproteinase domain. 
     
     
         14 . The method of  claim 1 , wherein the neuronal cells overexpress a FISH adaptor protein. 
     
     
         15 . The method of  claim 14 , further comprising a second group of neuronal cells which express a lower amount or no FISH adaptor protein. 
     
     
         16 . A method of treating or preventing Alzeihmer's disease in a patient comprising administering to a patient in need of prevention or treatment of Alzeihmer's disease, an effective amount of an agent that inhibits Aβ-induced cell death. 
     
     
         17 . A method of treating or preventing Alzeihmer's disease in a patient comprising administering to the patient a therapeutically effective amount of at least one agent, wherein the agent either:
 a) blocks phosphorylation of FISH; or   b) blocks cleavage of ADAM12.   
     
     
         18 . An isolated human homolog of a murine FISH protein, wherein the human homolog is phosphorylated in response to Aβ-induced cell death. 
     
     
         19 . The human homolog of  claim 18 , wherein the phosphorylation comprises tyrosine phosphorylation.