Effect of aging on roles of AMP-activated protein kinase for neuronal survival and function in hippocampus

Abstract

AMP-activated protein kinase (AMPK) controls energy status and regulates autophagic processes in response to various stresses, which are essential for metabolic homeostasis and cellular survival. Despite its pivotal roles in neuronal survival and functions, AMPK in aged brain has not been a target of the Aging Research. This study was conducted to elucidate the impact of aging on the physiological alterations and signaling of AMPK in the hippocampus of old mice. Results showed that activated AMPK and thioredoxin 1 (Trx1), a cofactor of AMPK, were significantly decreased and AMPK formed oxidized aggregates through intermolecular disulfide bonds in the hippocampus of old mice compared to that of young adult mice. Overexpression of Trx1 in the aged hippocampus by the viral-vector transfection successfully abolished the perinuclear aggregates of AMPK. It was also found that, in aged hippocampal neurons, mitochondria were abnormally clustered around the nucleus. The perinuclear clusters of mitochondria were co-localized with oxidized aggregates of AMPK and associated with significantly declined activation of ULK1, a protein kinase involved in the initiation of autophagosome formation and a direct substrate of AMPK phosphorylation. Overexpression of Trx1 successfully ameliorated activated ULK1 and effectively abolished abnormal perinuclear mitochondrial clustering in aged hippocampus. These findings indicate that chronic oxidative stresses during aging process impair the expression of Trx1 in aged hippocampus leading to oxidative aggregation of AMPK and consequent dysfunction of ULK1 causing deterioration of selective autophagic capacity being responsible for the clearance of defective mitochondria. The process was reversible and successfully recovered by over-expression of Trx1, which might be useful for future development of therapeutic strategies to overcome age-related hippocampal dysfunction.