Dysregulation of protein kinase a signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline.
Activation of the cAMP/protein kinase A (PKA) pathway has been proposed as a mechanism for improving age-related cognitive deficits based on studies of hippocampal function. However, normal aging also afflicts prefrontal cortical cognitive functioning. Here, we report that agents that increase PKA activity impair rather than improve prefrontal cortical function in aged rats and monkeys with prefrontal cortical deficits. Conversely, PKA inhibition ameliorates prefrontal cortical cognitive deficits. Western blot and immunohistochemical analyses of rat brain further indicate that the cAMP/PKA pathway becomes disinhibited in the prefrontal cortex with advancing age. These data demonstrate that PKA inhibition, rather than activation, is the appropriate strategy for restoring prefrontal cortical cognitive abilities in the elderly.
Ramos
Brian P
BP
Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Birnbaum
Shari G
SG
Lindenmayer
Isabelle
I
Newton
Samuel S
SS
Duman
Ronald S
RS
Arnsten
Amy F T
AF
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D018697:Nootropic Agents / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000494:pharmacology / Q000627:therapeutic use; D013873:Thionucleotides / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D018697:Nootropic Agents; D010726:Phosphodiesterase Inhibitors; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram