Osteocalcin as a treatment for cognitive disorders

Abstract

Methods and compositions for treating or preventing cognitive disorders in mammals, preferably humans, are provided. The methods generally involve modulation of the OST-PTP signaling pathway or the PTP-1B signaling pathway involving gamma-carboxylase and osteocalcin, e.g., by administratin of undercarboxylated/uncarboxylated osteocalcin. Disorders amenable to treatment by the methods include, but are not limited to, cognitive loss due to neurodegeneration associated with aging, anxiety, depression, memory loss, learning difficulties, and cognitive disorders associated with food deprivation during pregnancy.

1 . A method of treating or preventing a cognitive disorder in a mammal comprising administering to a mammal in need thereof a pharmaceutical composition comprising a therapeutically effective amount of undercarboxylated/uncarboxylated osteocalcin and a pharmaceutically acceptable carrier or excipient. 
     
     
         2 . The method of  claim 1  wherein the mammal is a human and the osteocalcin is human osteocalcin. 
     
     
         3 . The method of  claim 2  wherein the cognitive disorder is selected from the group consisting of cognitive loss due to neurodegeneration associated with aging, anxiety, depression, memory loss, learning difficulties, and cognitive disorders associated with food deprivation during pregnancy. 
     
     
         4 . The method of  claim 3  wherein the cognitive disorder is anxiety due to aging, depression due to aging, memory loss due to aging, or learning difficulties due to aging. 
     
     
         5 . The method of  claim 2  wherein at least one of
 (i) the undercarboxylated/uncarboxylated osteocalcin is a preparation of undercarboxylated/uncarboxylated osteocalcin in which more than about 20% of the total Glu residues at the positions corresponding to positions 17, 21 and 24 of mature human osteocalcin in the preparation are not carboxylated, 
 (ii) undercarboxylated/uncarboxylated osteocalcin shares at least 80% amino acid sequence identity with mature human osteocalcin when the undercarboxylated/uncarboxylated osteocalcin and mature human osteocalcin are aligned for maximum sequence homology, or 
 (iii) the undercarboxylated/uncarboxylated osteocalcin is a polypeptide selected from the group consisting of:
 (a) a fragment comprising mature human osteocalcin missing the last 10 amino acids from the C-terminal end; 
 (b) a fragment comprising mature human osteocalcin missing the first 10 amino acids from the N-terminal end; 
 (c) a fragment comprising amino acids 62-90 of SEQ ID NO:2; 
 (d) a fragment comprising amino acids 1-36 of mature human osteocalcin; 
 (e) a fragment comprising amino acids 13-26 of mature human osteocalcin; and 
 (f) a fragment comprising amino acids 13-46 of mature human osteocalcin. 
 
 
     
     
         6 . The method of  claim 5  wherein all three of the glutamic acids in the undercarboxylated/uncarboxylated osteocalcin at the positions corresponding to positions 17, 21 and 24 of mature human osteocalcin are not carboxylated. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 5  wherein the
 undercarboxylated/uncarboxylated osteocalcin shares about 98% amino acid sequence identity with mature human osteocalcin when the undercarboxylated/uncarboxylated osteocalcin and mature human osteocalcin are aligned for maximum sequence homology. 
 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 3  wherein the cognitive disorder is at least one of a cognitive loss due to neurodegeneration associated with aging, anxiety, depression, memory loss, or learning difficulties. 
     
     
         11 - 14 . (canceled) 
     
     
         15 . A method of diagnosing a cognitive disorder in a patient comprising:
 (i) determining a patient level of undercarboxylated/uncarboxylated osteocalcin in a biological sample taken from the patient;   (ii) comparing the patient level of undercarboxylated/uncarboxylated osteocalcin and a control level of undercarboxylated/uncarboxylated osteocalcin, and   (iii) if the patient level is significantly lower than the control level, then diagnosing the patient as having, or being at risk for, the cognitive disorder.   
     
     
         16 . The method of  claim 15  further comprising informing the patient or the patient's healthcare provider of the diagnosis. 
     
     
         17 . Use of a pharmaceutical composition comprising undercarboxylated/uncarboxylated osteocalcin for treating or preventing a cognitive disorder in a mammal. 
     
     
         18 . The use of  claim 17  wherein the mammal is a human and the osteocalcin is human osteocalcin. 
     
     
         19 . The use of  claim 18  wherein the cognitive disorder is selected from the group consisting of cognitive loss due to neurodegeneration associated with aging, anxiety, depression, memory loss, learning difficulties, and cognitive disorders associated with food deprivation during pregnancy. 
     
     
         20 . The use of  claim 19  wherein the cognitive disorder is anxiety due to aging, depression due to aging, memory loss due to aging, or learning difficulties due to aging. 
     
     
         21 . The use of  claim 18  wherein the undercarboxylated/uncarboxylated osteocalcin is a preparation of unmdercarboxylated/uncarboxylated osteocalcin in which more than about 20% of the total Glu residues at the positions corresponding to positions 17, 21 and 24 of mature human osteocalcin in the preparation are not carboxylated. 
     
     
         22 . The use of  claim 18  wherein all three of the glutamic acids in the undercarboxylated/uncarboxylated osteocalcin at the positions corresponding to positions 17, 21 and 24 of mature human osteocalcin are not carboxylated. 
     
     
         23 . The use of  claim 18  wherein the undercarboxylated/uncarboxylated osteocalcin shares at least 80% amino acid sequence identity with mature human osteocalcin when the undercarboxylated/uncarboxylated osteocalcin and mature human osteocalcin are aligned for maximum sequence homology. 
     
     
         24 . The use of  claim 23  wherein the undercarboxylated/uncarboxylated osteocalcin shares about 98% amino acid sequence identity with mature human osteocalcin when the undercarboxylated/uncarboxylated osteocalcin and mature human osteocalcin are aligned for maximum sequence homology. 
     
     
         25 . The use of  claim 18  wherein the undercarboxylated/uncarboxylated osteocalcin is a polypeptide selected from the group consisting of:
 (a) a fragment comprising mature human osteocalcin missing the last 10 amino acids from the C-terminal end; 
 (b) a fragment comprising mature human osteocalcin missing the first 10 amino acids from the N-terminal end; 
 (c) a fragment comprising amino acids 62-90 of SEQ ID NO:2; 
 (d) a fragment comprising amino acids 1-36 of mature human osteocalcin; 
 (e) a fragment comprising amino acids 13-26 of mature human osteocalcin; and 
 (f) a fragment comprising amino acids 13-46 of mature human osteocalcin. 
 
     
     
         26 . The use of  claim 19  wherein the cognitive disorder is at least one of cognitive loss due to neurodegeneration associated with aging, anxiety, depression, memory loss, or learning difficulties. 
     
     
         27 - 30 . (canceled)