Dysregulation of protein kinase a signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline

Neuron. 2003 Nov 13;40(4):835-45. doi: 10.1016/s0896-6273(03)00694-9.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism
  • Aging / drug effects
  • Aging / metabolism*
  • Animals
  • Cognition Disorders / drug therapy
  • Cognition Disorders / enzymology*
  • Cognition Disorders / physiopathology
  • Cyclic AMP / analogs & derivatives*
  • Cyclic AMP / pharmacology
  • Cyclic AMP / therapeutic use
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Enzyme Inhibitors / pharmacology
  • Macaca mulatta
  • Male
  • Memory Disorders / drug therapy
  • Memory Disorders / enzymology*
  • Memory Disorders / physiopathology
  • Nootropic Agents / pharmacology
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphodiesterase Inhibitors / therapeutic use
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / enzymology*
  • Prefrontal Cortex / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Rolipram / pharmacology
  • Rolipram / therapeutic use
  • Thionucleotides / pharmacology
  • Thionucleotides / therapeutic use
  • Up-Regulation / drug effects
  • Up-Regulation / physiology

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Nootropic Agents
  • Phosphodiesterase Inhibitors
  • Thionucleotides
  • adenosine-3',5'-cyclic phosphorothioate
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Rolipram