Leptin as an anti- amyloidogenic biologic and methods for delaying the onset and reducing alzheimer's disease-like pathology

Abstract

The present invention relates to methods for treating, preventing, or diagnosing the pathology of progressive cognitive disorders resulting from accumulation of an amyloid peptide, in particular, Alzheimer's disease, Down's syndrome and cerebral amyloid angiopathy, in mammalian subjects using a composition comprising therapeutically effective amount of a leptin, leptin mimic, leptin derivative, leptin agonist, or AMP-dependent protein kinase activator, alone, or in combination with, one or more lipolytic/antilipogenic compounds. It further relates to methods for improving cognitive function using a composition comprising a therapeutically effective amount of leptin, a leptin mimic, a leptin derivative, an AMP-dependent protein kinase activator, a leptin agonist, a leptin blocker, a mimic of a leptin blocker, a leptin antagonist, an AMP-dependent protein kinase inhibitor; or a pharmaceutically acceptable salt thereof.

1 . A method for treating a progressive cognitive disease, cognitive disorder, or cognitive condition resulting from accumulation of an amyloid peptide, comprising:
 administering to a subject in need thereof a first composition comprising   (i) a therapeutic amount of a leptin, a leptin mimic, or a pharmaceutically acceptable salt thereof, and   (ii) a pharmaceutically acceptable carrier,   wherein the leptin or the leptin mimic is a recombinant human leptin, a pegylated recombinant human leptin (PEG-OB), a recombinant human methionyl leptin, a leptin peptidomimetic, a biologically active fragment of leptin, a fusion peptide of leptin with an Fc fragment of immunoglobulin, a fusion peptide of the biologically-active fragment of leptin with the Fc fragment of immunoglobulin, a leptin agonist, or a combination thereof.   wherein the therapeutic amount of the leptin or the leptin mimic is effective to modulate accumulation of the amyloid peptide in brain.   
     
     
         2 . The method according to  claim 1 , wherein the method further comprises monitoring circulating levels of the amyloid peptide. 
     
     
         3 . The method according to  claim 2 , wherein the circulating levels of amyloid peptide are detected in a sample of cerebrospinal fluid or blood. 
     
     
         4 . The method according to  claim 1 , wherein the method further comprises placing the subject on a low fat diet. 
     
     
         5 . The method according to  claim 1 , wherein the progressive cognitive disease, cognitive disorder, or cognitive condition is a dementia, an amyloidosis, Down's syndrome, or cerebral amyloid angiopathy. 
     
     
         6 . The method according to  claim 5 , wherein the progressive cognitive disease, cognitive condition, or cognitive disorder is Alzheimer's disease. 
     
     
         7 . The method according to  claim 6 , wherein the progressive cognitive disease, cognitive condition, or cognitive disorder is senile systemic amyloidosis. 
     
     
         8 . The method according to  claim 5 , wherein the progressive cognitive disease, cognitive condition, or cognitive disorder is cerebrovascular amyloidosis. 
     
     
         9 . The method according to  claim 1 , wherein the amyloid peptide is an amyloid β (Aβ) peptide. 
     
     
         10 . The method according to  claim 1 , wherein the first composition further comprises
 (iii) a therapeutically effective amount of one or more lipolytic/antilipogenic compounds wherein the one or more lipolytic/antilipogenic compounds reduce amyloid β (Aβ) production, increase apoE-Aβ (Aβ) uptake, or both.   
     
     
         11 . (canceled) 
     
     
         12 . The method according to  claim 1 , wherein the first composition modulates accumulation of the amyloid peptide in the cerebral nervous system. 
     
     
         13 . The method according to  claim 1 , wherein the first composition is administered by at least one route selected from the group consisting of orally, buccally, parenterally, intranasally, rectally, and topically. 
     
     
         14 . The method according to  claim 1 , wherein the method further comprises serially administering a second composition comprising a therapeutically effective amount of one or more lipolytic/antilipogenic compounds, wherein the one or more lipolytic/antilipogenic compounds reduce amyloid β (Aβ) production, increase apoE-Aβ (Aβ) uptake, or both. 
     
     
         15 . (canceled) 
     
     
         16 . The method according to  claim 14 , wherein the method further comprises placing the subject on a low fat diet. 
     
     
         17 . (canceled) 
     
     
         18 . A method of improving resilience of cognitive function in a subject in need thereof, the method comprising
 (a) administering to the subject a composition comprising:
 i. a cognitive function-enhancing or cognitive function stabilizing amount of leptin, a leptin mimic or a pharmaceutically acceptable salt thereof, 
   wherein the leptin or the leptin mimic is a recombinant human leptin, a pegylated recombinant human leptin (PEG-OB), a recombinant human methionyl leptin, a leptin peptidomimetic, a biologically-active fragment of leptin, a fusion peptide of leptin with an Fc fragment of immunoglobulin, a fusion peptide of the biologically-active fragment of leptin with the Fc fragment of immunoglobulin, a leptin agonist, and a combination thereof, and   ii. a pharmaceutically acceptable carrier   wherein the cognitive function-enhancing or the cognitive function stabilizing amount of leptin or the leptin mimic is effective to modulate accumulation of an amyloid peptide in brain.   
     
     
         19 . The method according to  claim 18 , wherein the composition is administered orally, buccally, parenterally, intranasally, rectally, or topically. 
     
     
         20 . The method according to  claim 18 , further comprising
 (b) measuring the subject's ability to perform mental tasks.   
     
     
         21 . The method according to  claim 20 , wherein the subject's ability to perform mental tasks is measured by at least one test for memory, computation, or attention. 
     
     
         22 . The method according to  claim 1 , wherein the biologically active fragment of leptin comprises an amino acid sequence selected from the group consisting of SEQ in NOs: 27-40. 
     
     
         23 . The method according to  claim 1 , wherein the biologically active fragment of leptin comprises a first and a second fragment,
 wherein the first fragment has amino acid sequence SEQ ID NO: 41,   wherein the second fragment has amino acid sequence SEQ ID NO: 42, and   wherein the first fragment is covalently linked to the second fragment via a disulfide bond between cysteine at amino acid residue 96 of SEQ ID NO: 41 and cysteine at amino acid residue 8 of SEQ ID NO: 42.   
     
     
         24 . The method according to  claim 1 , wherein the therapeutic amount is from about 0.01 mg per kg (of body weight) per day to about 0.5 mg per kg (of body weight) per day. 
     
     
         25 . The method according to  claim 1 , wherein the subject in need thereof has a systemic leptin deficiency. 
     
     
         26 . The method according to  claim 25 , wherein the composition restores, replenishes, or increases leptin levels. 
     
     
         27 . The method according to  claim 18 , wherein the biologically active fragment of leptin has an amino acid sequence selected from the group consisting of SEQ ID NOs: 27-40. 
     
     
         28 . The method according to  claim 18 , wherein the biologically active fragment of leptin comprises a first and a second fragment,
 wherein the first fragment has amino acid sequence SEQ ID NO: 41,   wherein the second fragment has amino acid sequence SEQ ID NO: 42, and   wherein the first fragment is covalently linked to the second fragment via a disulfide bond between cysteine at amino acid residue 96 of SEQ ID NO: 41 and cysteine at amino acid residue 8 of SEQ ID NO: 42.   
     
     
         29 . The method according to  claim 18 , wherein the cognitive function-enhancing amount of the leptin, the leptin mimic, or the pharmaceutically acceptable salt thereof, reduces amyloid β (Aβ) production, increases apoE-Abeta (Aβ) uptake, or both. 
     
     
         30 . The method according to  claim 18 , wherein the amyloid peptide is an amyloid β (Aβ) peptide. 
     
     
         31 . The method according to  claim 18 , wherein the subject in need thereof has a systemic leptin deficiency. 
     
     
         32 . The method according to  claim 31 , wherein the composition restores, replenishes, or increases leptin levels. 
     
     
         33 . The method according to  claim 18 , wherein the cognitive function-enhancing amount is from about 0.01 mg per kg (of body weight) per day to about 0.5 mg per kg (of body weight) per day. 
     
     
         34 . The method according to  claim 18 , wherein the composition further comprises
 (iii) a therapeutically effective amount of one or more lipolytic/antilipogenic compounds, wherein the one or more lipolytic/antilipogenic compounds reduce amyloid β (Aβ) production, increase apoE-Aβ (Aβ) uptake, or both.   
     
     
         35 . The method according to  claim 18 , wherein the method further comprises placing the subject on a low fat diet. 
     
     
         36 . The method according to  claim 18 , wherein the method further comprises serially administering a second composition comprising a therapeutically effective amount of one or more lipolytic/antilipogenic compounds, wherein the one or more lipolytic/antilipogenic compounds reduce amyloid β (Aβ) production, increase apoE-Aβ (Aβ) uptake, or both.