Methods for characterizing and treating cognitive impairment in aging and disease

Abstract

This invention provides methods for identifying genes associated with cognitive impairment and for identifying compounds useful in the treatment of cognitive impairment. The methods can in particular be used to identify genes associated with, and compounds useful in treating, cognitive impairment in aging.

1 - 42 . (canceled) 
     
     
         43 . A pharmaceutical composition for treating cognitive impairment, the composition comprising a pharmaceutically effective amount of a GABA-A α5 receptor agonist and a pharmaceutically acceptable carrier,
 wherein the GABA-A α5 receptor agonist is characterized in that it significantly increases the abundance or enhances the function of the GABA-A α5 receptor gene (GENBANK® accession number NM_017295), its homologues, or its expressed gene product in a mammalian cell to which the candidate compound is administered. 
 
     
     
         44 . The pharmaceutical composition according to  claim 43 , wherein the agonist is selected from the group consisting of 1-methyl-7-acetyleno-5-phenyl-1,3-dihydro-benzo[e]-1,4-diazepin-2-one, 6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one, and 8-ethylthio-3-methyl-5-(1-oxidopyridin-2-yl)-3,4-dihydronaphthalen-1(2H)-one. 
     
     
         45 . The pharmaceutical composition according to  43 , wherein the mammalian cell is selected from the group consisting of a neuronal cell and a glial cell. 
     
     
         46 . The pharmaceutical composition according to  claim 45 , wherein the mammalian cell is a hippocampal cell. 
     
     
         47 . The pharmaceutical composition according to  claim 46 , wherein the hippocampal cell is selected from the group of a CA1 cell, a CA3 cell or a DG cell. 
     
     
         48 . The pharmaceutical composition according to any one of  claims 43 ,  45  and  46 , wherein the mammalian cell is from an aged mammal. 
     
     
         49 . The pharmaceutical composition according to  claim 48 , wherein the aged mammal is cognitively impaired. 
     
     
         50 . A pharmaceutical composition for treating cognitive impairment, the composition comprising a pharmaceutically effective amount of a GABA-A α5 receptor agonist and a pharmaceutically acceptable carrier,
 wherein the GABA-A α5 receptor agonist is characterized in that it significantly increases the abundance or enhances the function of the GABA-A α5 receptor gene (GENBANK® accession number NM_017295), its homologues, or its expressed gene product in an aged mammal with cognitive impairment to whom the compound is administered relative to a member of a group consisting of an aged mammal without cognitive impairment, a young mammal, an aged cognitively impaired mammal in the absence of the compound, and two or more of them. 
 
     
     
         51 . A pharmaceutical composition for treating cognitive impairment, the composition comprising pharmaceutically effective amount of a GABA-A α5 receptor agonist and a pharmaceutically acceptable carrier,
 wherein the GABA-A α5 receptor agonist is characterized in that it significantly increases the abundance or enhances the function of the GABA-A α5 receptor gene (GENBANK® accession number NM_017295), its homologues, or its expressed gene product, and 
 wherein the GABA-A α5 receptor agonist beneficially alters the cognitive status of a mammal to whom the compound is administered relative to a member of a group consisting of an aged mammal without cognitive impairment, a young mammal, an aged cognitively impaired mammal in the absence of the compound, and two or more of them. 
 
     
     
         52 . The pharmaceutical composition according to  claim 51 , wherein the composition does not significantly alter the cognitive status of a member of the group consisting of a young mammal, an aged cognitively unimpaired mammal, and both, to whom the compound is administered. 
     
     
         53 . The pharmaceutical composition according to  claim 50  or  51 , wherein said cognitive function is hippocampal-dependent function. 
     
     
         54 . The pharmaceutical composition according to  claim 53 , wherein the hippocampal-dependent function is selected from the group consisting of spatial memory acquisition, long-term spatial memory, and spatial memory retrieval. 
     
     
         55 . The pharmaceutical composition according to any one of  claims 48 - 52 , wherein the mammal is an outbred strain of rat. 
     
     
         56 . The pharmaceutical composition according to any one of  claims 48 - 52 , wherein the mammal is a human. 
     
     
         57 . The pharmaceutical composition according to  claim 43 ,  50  or  51 , wherein the abundance is determined in CA1, CA3 or DG hippocampal tissue.