AMPK agonist AICAR improves cognition and motor coordination in young and aged mice

Abstract

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 a2-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.

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

“…Some studies showed that systemic administration of the AMPK agonist AICAR increased spatial memory and improved motor function in young and old female mice (Kobilo et al, 2014;Kobilo et al, 2011). Other studies found that the activation of AMPK impaired long-term spatial memory (Dash et al, 2006).…”

“…Several studies showed that AMPK has a crucial role in cognitive decline and memory dysfunction, which are the most characteristic symptoms of Alzheimer's disease (DiTacchio et al, 2015;Du et al, 2015). Although inconsistent findings have been reported regarding the role of AMPK in the formation of spatial memory (Dash et al, 2006;Kobilo et al, 2014;Kobilo et al, 2011), these findings indicate that AMPK activity is involved in learning and memory processes. However, little is known about the role of AMPK activity in the hippocampus in contextual fear memory formation.…”

Inhibition of glycogen synthase kinase-3β enhances cognitive recovery after stroke: the role of TAK1

“…The mechanisms by which acute AMPK activation increases ischemic damage remains unclear, but increased glucose uptake due to unregulated glucose transporters in the reperfusion phase, enhanced lactate accumulation, and increased autophagy likely contribute to increased neuronal death after ischemic reperfusion (McCullough et al 2005;Li et al 2007;Arsikin et al 2012). A recent study has shown that GSK-3b acts as a critical sensor for anabolic signaling and regulates AMPK; others have found that AMPK activation mediates learning and memory (Suzuki et al 2013;Kobilo et al 2014). To address the role of AMPK in the neuroprotective and cognitive benefit of GSK-3b inhibition, we treated AMPK-a2 deficient mice with GSK-3b inhibitor VIII.…”

Exercise Training Prevents Age-induced Insulin Resistance in Rats: Effect on Circulating Catecholamines, Inflammatory Cytokines and Skeletal Muscle Glut4 Transporters

“…The enhanced circulating catecholamines ultimately lead to insulin resistance [8] . The ability to control the blood glucose level progressively reduces during the life span [17,18] . A gradual decline in skeletal muscle glucose uptake was observed during the phase of growth [18,19] .…”

“…The ability to control the blood glucose level progressively reduces during the life span [17,18] . A gradual decline in skeletal muscle glucose uptake was observed during the phase of growth [18,19] . Variations of glucose transporters (GLUTs) in the skeletal muscle have been reported, namely, the glucose transporter type 4 (GLUT4).…”