Neurotoxic target for amylospheroid, method and material for reducing the neurotoxicity of amylospheroid, and use thereof

Abstract

In one or a plurality of embodiments, there is provided a target molecule of amylospheroid, which is expressed in mature neurons and to which the amylospheroid binds to induce death of cells. Further, in one or a plurality of embodiments, there is provided a method and a substance for inhibiting death of mature neurons induced by the amylospheroid. In one aspect, the present disclosure relates to a use of Na − /K + −ATPase α3 as a binding target molecule of amylospheroid. In another aspect, the present disclosure relates to a method for suppressing death of mature neurons induced by the amylospheroid, including inhibiting protein-protein interaction between the amylospheroid and the Na + /K + −ATPase α3, and the like.

1 - 10 . (canceled) 
     
     
         11 . A method for screening a candidate compound of an effective component of a pharmaceutical composition for preventing, ameliorating, and/or treating Alzheimer's disease and/or dementia with Lewy bodies, comprising:
 measuring an inhibiting capacity of protein-protein interaction between amylospheroid and Na + /K + −ATPase α3 through use of a test compound; and   selecting the candidate compound based on a result of the measurement.   
     
     
         12 . A method for screening a candidate compound of an effective component of a pharmaceutical composition for preventing, ameliorating, and/or treating Alzheimer's disease and/or dementia with Lewy bodies, comprising:
 measuring an inhibiting capacity of protein-protein interaction between amylospheroid and Na + /K + −ATPase α3, and/or binding ability with respect to the amylospheroid, and/or a suppressive capacity with respect to death of a mature neuron induced by the amylospheroid, using a test compound synthesized by performing Structure-Based Drug Design based on a tertiary structure of an extracellular domain 4 of Na + /K + −ATPase α3 or a part thereof; and   selecting the candidate compound based on a result of the measurement.   
     
     
         13 . A method for diagnosing a clinical condition of Alzheimer's disease and/or Lewy body dementia, comprising:
 detecting a signal of an Na + /K + −ATPase α3 imaging probe including a binding partner of Na + /K + −ATPase α3 as a binding portion with respect to the Na + /K + −ATPase α3 from a subject to which the imaging probe has been administered; and   determining severity of a clinical condition of Alzheimer's disease and/or dementia with Lewy bodies based on signal data or image data of the signal or a result of measurement of an Na + /K + −ATPase α3 amount calculated from the signal data or the image data.   
     
     
         14 . A method for checking severity of a clinical condition of Alzheimer's disease and/or dementia with Lewy bodies of a subject, comprising:
 detecting a signal of an Na + /K + −ATPase α3 imaging probe including a binding partner of Na + /K + −ATPase α3 as a binding portion with respect to the Na + /K + −ATPase α3 from the subject to which the imaging probe has been administered; and   measuring an Na + /K + −ATPase α3 amount calculated from signal data or image data of the signal; and   comparing a result of the measurement with a standard in which the severity is determined to be higher as the measured Na + /K + −ATPase α3 amount is lower than an Na + /K + −ATPase α3 amount of a normal individual, and/or the severity is determined to be higher/lower, respectively, in a case where the measured Na + /K + −ATPase α3 amount is higher/lower than a previous Na + /K + −ATPase α3 amount of the subject.   
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . A synthesized, isolated, or purified polypeptide, comprising a motif represented by an amino acid sequence of the following Formula (I), (II), or (III):
 X 1 X 2 X 3 X 4  (I) (SEQ ID NO: 7)   X 2 X 3 X 4 X 5  (II) (SEQ ID NO: 43)   X 2 X 3 X 4  (SEQ ID NO: 48)   where X 1  is arginine (Arg), histidine (His), or lysine (Lys),   X 2  is a hydrophobic amino acid residue or glycine (Gly),   X 3  is asparagine (Asn), glutamine (Gln), serine (Ser), threonine (Thr), cysteine (Cys), histidine (His), or Tyr (tyrosine),   X 4  is tryptophan (Trp), phenylalanine (Phe), or tyrosine (Tyr), and   X 5  is tryptophan (Trp), tyrosine (Tyr), aspartic acid (Asp), or a hydrophobic amino acid residue, the polypeptide having binding ability with respect to amylospheroid.   
     
     
         18 . A polypeptide according to  claim 17 , comprising a motif represented by an amino acid sequence of the Formula (I), (II), or (III) at an N-terminal. 
     
     
         19 . A polypeptide according to  claim 17 , wherein the amino acid sequence has a length of 4 to 25 amino acids. 
     
     
         20 . A polypeptide according to  claim 17 , which is capable of inhibiting interaction between the amylospheroid and Na − /K + −ATPasesα3, and/or suppressing death of a mature cell induced by the amylospheroid. 
     
     
         21 . A polypeptide according to  claim 17 , which is similar in structure to an extracellular domain 4 of Na + /K + −ATPase α3 or a part thereof 
     
     
         22 . A polypeptide according to  claim 21 , which is similar in structure to a portion in which an amino acid sequence in the extracellular domain 4 of the Na + /K + −ATPase α3 is RLNW (SEQ ID NO: 1). 
     
     
         23 . A peptide mimetic similar in structure to the polypeptide according to  claim 17 , which is capable of inhibiting interaction between the amylospheroid and Na + /K + −ATPasesα3, and/or suppressing death of a mature neuron induced by the amylospheroid. 
     
     
         24 . A polynucleotide encoding the polypeptide according to  claim 17 . 
     
     
         25 . A vector for expressing the polypeptide according to  claim 17 , comprising a polynucleotide encoding the polypeptide. 
     
     
         26 . A composition comprising the polypeptide according to  claim 17 . 
     
     
         27 . A composition according to  claim 26 , used for detecting and/or measuring the amylospheroid. 
     
     
         28 . A composition according to  claim 26  used for suppressing death of a mature neuron induced by the amylospheroid. 
     
     
         29 . A composition according to  claim 26 , used for inhibiting interaction between the amylospheroid and Na + /K + −ATPase α3. 
     
     
         30 . A pharmaceutical composition comprising the polypeptide according to  claim 17 . 
     
     
         31 . A pharmaceutical composition according to  claim 30 , used for preventing, ameliorating, and/or treating Alzheimer's disease and/or dementia with Lewy bodies. 
     
     
         32 . A probe with respect to amylospheroid or a precursor thereof, comprising the polypeptide according to  claim 17 . 
     
     
         33 . A probe or a precursor thereof according to  claim 32 , used for imaging the amylospheroid, or detecting or measuring the amylospheroid. 
     
     
         34 . An amylospheroid imaging method, comprising detecting a signal of an amylospheroid imaging probe including the polypeptide according to  claim 17 . 
     
     
         35 . A method for measuring an amylospheroid amount, comprising calculating an amylospheroid amount based on signal data or image data obtained by the amylospheroid imaging method according to  claim 34 . 
     
     
         36 - 39 . (canceled)