Leptin Compositions and Methods for Treating Progressive Cognitive Function Disorders Resulting from Accumulation of Neurofibrillary Tangles and Amyloid Beta

Abstract

The present disclosure provides compositions containing a leptin product and methods of clinical therapy and diagnostic methods for progressive cognitive disorders. According to one aspect, the described invention provides a method for treating a progressive cognitive disorder. According to another aspect, the described invention provides a method for improving resilience of cognitive function in a subject in need thereof. According to another aspect, the described invention provides a method for identifying an effective therapeutic agent for treating a progressive cognitive dysfunction disease or disorder that results from at least one of accumulation of Aβ, hyperphosphorylation of tau, or accumulation of neurofibrillary tangles.

What is claimed is: 
     
         1 - 43 . (canceled) 
     
     
         44 . A method for improving cognitive function of subject suffering from at least one symptom of cognitive impairment comprising administering to the subject suffering from the at least one symptom of cognitive impairment a therapeutic amount of a leptin composition comprising:
 a. a leptin as a first therapeutic agent;   b. optionally, at least one second therapeutic agent comprising a kinase modulator; and   c. a pharmaceutically acceptable carrier;
 wherein the therapeutic amount of the leptin composition is effective to improve cognitive function of the subject by reducing at least one of:
 (1) the extracellular accumulation of amyloid beta in brain tissue, relative to the accumulation of amyloid beta in brain tissue of a subject treated with placebo, 
 (2) the amount of abnormally phosphorylated tau in brain, relative to the amount of abnormally phosphorylated tau observed in a subject treated with placebo, and 
 (3) the accumulation of neurofibrillary tangles in brain tissue, relative to the accumulation of neurofibrillary tangles observed in a subject treated with placebo, 
 
 wherein the symptom of cognitive impairment is further characterized
 (1) as an impairment in memory, an impairment in language skill, an impairment in perceptual skills, an impairment in attention, an impairment in constructive ability, an impairment in orientation ability, an impairment in problem solving ability, an impairment in functional ability, or a combination thereof, as compared to a healthy subject, and 
 (2) associated with at least one of (a) the extracellular accumulation of amyloid beta in brain tissue, (b) the aberrant pattern of phosphorylation of a tau protein in brain tissue, and (c) the accumulation of neurofibrillary tangles in brain tissue. 
 
   
     
     
         45 . The method according to  claim 44 , wherein the abnormal phosphorylation of tau is at least one phosphorylation site selected from the group consisting of Ser 181 , Ser 202 , Thr 205 , Ser 212 , Ser 214 , Thr 231 , Ser 235 , Ser 396 , and Ser 404 . 
     
     
         46 . The method according to  claim 44 , wherein the kinase modulator is an activator of 5′adenosine monophosphate (AMP)-activated protein kinase (AMPK). 
     
     
         47 . The method according to  claim 46 , wherein the activator of 5′adenosine monophosphate (AMP)-activated protein kinase (AMPK) is 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR). 
     
     
         48 . The method according to  claim 44 , wherein the kinase modulator is at least one kinase inhibitor of Glycogen Synthase Kinase-3 beta (GSK-3β). 
     
     
         49 . The method according to  claim 48 , wherein the at least one kinase inhibitor of Glycogen Synthase Kinase-3 beta (GSK-3β) is selected from the group consisting of Lithium Chloride, 6-bromoindirubin-3′-oxime ((2′Z,3′E)-6-bromoindirubin-3′-oxime, 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione, and TDZD-8 (4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione-8). 
     
     
         50 . The method according to  claim 44 , wherein the therapeutic amount of the leptin in the leptin composition is an amount from about 0.0001 mg/kg body weight to about 100 g/kg body weight. 
     
     
         51 . The method according to  claim 44 , wherein at least one symptom of cognitive impairment is associated with at least one disease selected from the group consisting of Alzheimer's Disease, cerebral amyloid angiopathy, Down's Syndrome, progressive supranuclear palsy; a dementia;
 Creutzfeldt-Jacob disease, frontotemporal dementia, Pick's disease, Frontotemporal Dementia with Parkinsonism-17 corticobasal degeneration, frontotemporal lobe degeneration; Huntington's Disease; and Parkinson's Disease.