Diagnosis methods, diagnostic agents, and therapeutic agents against alzheimer's disease and frontotemporal lobar degeneration, and screening methods for these agents

Abstract

It has been revealed that, from a pre-onset stage of Alzheimer's disease, enhancement of phosphorylations of MARCKS and the like causes abnormal spine formation or the like, consequently developing the disease. It also has been revealed that the phosphorylations of MARCKS and the like are caused by PKC and the like, and further that b-raf is involved in phosphorylation of tau protein important for the progression of Alzheimer's disease. Thus, these proteins have been found to be target molecules useful in the diagnosis and treatment of Alzheimer's disease. In addition, it has also been revealed that, in a pre-onset stage of frontotemporal lobar degeneration, b-RAF phosphorylation enhancement causes a decrease in the number of spines and the like, consequently developing the disease. Thus, b-RAF has been found to be a target molecule useful in the diagnosis and treatment of frontotemporal lobar degeneration.

1 . A method for diagnosing Alzheimer's disease of a test subject, the method comprising:
 (i) a step of detecting an activity or expression of a kinase protein in the test subject;   (ii) a step of comparing the activity or expression with an activity or expression of a kinase protein in a normal subject; and   (iii) a step of determining that the test subject is affected with Alzheimer's disease or has a risk of developing Alzheimer's disease if the activity or expression of the kinase protein in the test subject is higher than the activity or expression of the kinase protein in the normal subject as a result of the comparison,   wherein the kinase protein is one or more kinase protein selected from the group consisting of PKC, CaMK, CSK, Lyn, and b-RAF.   
     
     
         2 . An agent for diagnosing Alzheimer's disease, the agent comprising a compound having an activity of binding to one or more kinase protein selected from the group consisting of PKC, CaMK, CSK, Lyn, and b-RAF. 
     
     
         3 . A screening method for a candidate compound for diagnosing Alzheimer's disease, the method comprising the steps of:
 bringing a test compound into contact with one or more kinase protein selected from the group consisting of PKC, CaMK, CSK, Lyn, and b-RAF; and   selecting the compound if the compound binds to the kinase protein.   
     
     
         4 . An agent for treating Alzheimer's disease, the agent comprising a compound capable of suppressing an activity or expression of one or more kinase protein selected from the group consisting of PKC, CaMK, CSK, Lyn, and b-RAF. 
     
     
         5 . The agent according to  claim 4 , wherein the compound is capable of suppressing an activity or expression of b-RAF and is one or more compound selected from the group consisting of PLX-4720, sorafenib, GDC-0879, vemurafenib, dabrafenib, sorafenib tosylate, and LGX818. 
     
     
         6 . The agent according to  claim 5 , wherein the compound is vemurafenib. 
     
     
         7 . An agent for treating Alzheimer's disease, the agent comprising a compound capable of suppressing a binding of one or more substrate protein selected from the group consisting of MARCKS, Marcksl1, SRRM2, SPTA2, ADDB, NEUM, BASP1, SYT1, G3P, HS90A, CLH, NFH, NFL, GPRIN1, ACON, ATPA, and ATPB to one or more kinase protein selected from the group consisting of PKC, CaMK, CSK, Lyn, and b-RAF. 
     
     
         8 . A screening method for a candidate compound for treating Alzheimer's disease, the method comprising:
 (i) a step of applying a test compound to a system capable of detecting an activity or expression of one or more kinase protein selected from the group consisting of PKC, CaMK, CSK, Lyn, and b-RAF; and   (ii) a step of selecting the compound if the compound suppresses the activity or expression of the protein.   
     
     
         9 . A screening method for a candidate compound for treating Alzheimer's disease, the method comprising the following steps (a) to (c):
 (a) a step of bringing one or more kinase protein selected from the group consisting of PKC, CaMK, CSK, Lyn, and b-RAF into contact with one or more substrate protein selected from the group consisting of MARCKS, Marcksl1, SRRM2, SPTA2, ADDB, NEUM, BASP1, SYT1, G3P, HS90A, CLH, NFH, NFL, GPRIN1, ACON, ATPA, and ATPB, in the presence of a test compound;   (b) a step of detecting a binding between the kinase protein and the substrate protein; and   (c) a step of selecting the test compound if the test compound suppresses the binding.