Screening methods using fyn in combination with tau protein

Abstract

The present invention provides materials and methods relating to screening for compounds useful in the treatment of Alzheimer's disease and related conditions. In particular, screening methods using tyrosine kinases are provided, as are methods relating to the role of tyrosine kinases as therapeutic targets.

1 - 51 . (canceled) 
     
     
         52 . A method of treating or preventing a tauopathy, the method comprising:
 (a) screening for a substance which is a candidate therapeutic agent for treating a tauopathy, said substance being effective to inhibit the phosphorylation of a tau protein by a tyrosine kinase, wherein the tau protein comprises at least one phosphorylation site, comprising:
 (i) contacting at least one said substance, the tau protein and the tyrosine kinase under in vitro conditions in which the tyrosine kinase is capable of phosphorylating said at least one phosphorylation site of the tau protein in the absence of the substance; 
 (ii) detecting whether the substance inhibits the phosphorylation of the tau protein at said at least one phosphorylation site of the tau protein by the tyrosine kinase; and 
 (iii) selecting the substance which inhibits phosphorylation of the tau protein at said at least one phosphorylation site; and 
   (b) administering the substance selected by screening step (a) to a patient in a therapeutically or prophylactically effective amount;   wherein the tyrosine kinase is Fyn and the tau protein is a protein which undergoes phosphorylation by Fyn and has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 1, or a fragment of said tau protein, said fragment comprising at least 25 amino acids and including at least one said phosphorylation site; and   wherein the tauopathy is selected from the group consisting of Alzheimer's Disease (AD), frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Pick's disease, corticobasal degeneration and multiple system atrophy (MSA).   
     
     
         53 . The method of  claim 52 , wherein the substance obtained from screening step (a) is effective to inhibit the phosphorylation of residues Y 18 F and/or Y 310 F on the tau protein. 
     
     
         54 . The method of  claim 52 , wherein the detecting step further comprises determining the extent of the inhibition of the phosphorylation of the tau protein. 
     
     
         55 . The method of  claim 52 , wherein the tau protein is paired helical filament tau. 
     
     
         56 . The method of  claim 52 , wherein the tau protein has greater than 90% sequence identity with the tau protein comprising the amino acid sequence set out in SEQ ID NO: 1. 
     
     
         57 . The method of  claim 52 , wherein the tau protein comprises the amino acid sequence set out in SEQ ID NO: 1. 
     
     
         58 . The method of  52 , wherein the tau protein is a fragment of the tau protein comprising the amino acid sequence set out in SEQ ID NO: 1. 
     
     
         59 . The method of  claim 52  wherein the step of detecting the presence or absence of phosphorylation at one or more sites of the tau protein employs mass spectroscopy.