AMPK agonist AICAR improves cognition and motor coordination in young and aged mice.
Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging-associated frailty can preclude physical activity. In young sedentary animals, pharmacological activation of AMP-activated protein kinase (AMPK), a transcriptional regulator important for muscle physiology, enhanced spatial memory function, and endurance. In the present study we investigated effects of AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) on memory and motor function in young (5- to 7-wk-old) and aged (23-mo-old) female C57Bl/6 mice, and in young (4- to 6-wk-old) transgenic mice with muscle-specific mutated AMPK α2-subunit (AMPK-DN). Mice were injected with AICAR (500 mg/kg) for 3-14 d. Two weeks thereafter animals were tested in the Morris water maze, rotarod, and open field. Improved water maze performance and motor function were observed, albeit at longer duration of administration, in aged (14-d AICAR) than in young (3-d AICAR) mice. In the AMPK-DN mice, the compound did not enhance behavior, providing support for a muscle-mediated mechanism. In addition, microarray analysis of muscle and hippocampal tissue derived from aged mice treated with AICAR revealed changes in gene expression in both tissues, which correlated with behavioral effects in a dose-dependent manner. Pronounced up-regulation of mitochondrial genes in muscle was observed. In the hippocampus, genes relevant to neuronal development and plasticity were enriched. Altogether, endurance-related factors may mediate both muscle and brain health in aging, and could play a role in new therapeutic interventions.
Neuroplasticity and Behavior Unit, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Tali
T
Kobilo
Davide
D
Guerrieri
Yongqing
Y
Zhang
Sarah C
SC
Collica
Kevin G
KG
Becker
Henriette
H
van Praag
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000375:Aging / Q000187:drug effects* / Q000502:physiology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects*; D012263:Ribonucleosides / Q000494:pharmacology*; D013028:Space Perception / Q000187:drug effects; D013997:Time Factors
D002491:Central Nervous System Agents; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases