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Schubert, D. Glucose metabolism and Alzheimer's disease. Ageing Res. Rev. 4, 240-257

Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 N, Torrey Pines Road, La Jolla, CA 92037, USA.
Ageing Research Reviews (Impact Factor: 4.94). 06/2005; 4(2):240-57. DOI: 10.1016/j.arr.2005.02.003
Source: PubMed

ABSTRACT

The brain is the organ with the highest basal rate of glucose consumption. Most of the energy generated by the oxidation of glucose is used for the work necessary to maintain the ionic balances associated with synaptic transmission. When the nervous system is subjected to the oxidative stress of age-associated disease, there is a redistribution of glucose breakdown to pathways that more efficiently produce molecules involved in antioxidant metabolism. This shift is at least in part mediated by the transcription factor HIF-1. The clinical implications of this change in glucose metabolism are discussed in the context of aging and Alzheimer's disease.

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    • "In light of the recent report that the G6PD activity can be regulated by reversible tyrosine phosphorylation [49], whether AMPK can activate the G6PD by post-translational modification to increase NADPH production is worthy of further investigation. Although glycolysis and PPP are parallel pathways in glucose metabolism , the redistribution of glycolytic flux can regulate the PPP activity for the generation of NADPH [21] [22]. The findings of this study further suggest that the increase of glycolytic flux exerted by AMPK activation can regulate the intracellular NADPH production. "
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    ABSTRACT: Background: Mitochondrial DNA (mtDNA) mutations are an important cause of mitochondrial diseases, for which there is no effective treatment due to complex pathophysiology. It has been suggested that mitochondrial dysfunction-elicited reactive oxygen species (ROS) plays a vital role in the pathogenesis of mitochondrial diseases, and the expression levels of several clusters of genes are altered in response to the elevated oxidative stress. Recently, we reported that glycolysis in affected cells with mitochondrial dysfunction is upregulated by AMP-activated protein kinase (AMPK), and such an adaptive response of metabolic reprogramming plays an important role in the pathophysiology of mitochondrial diseases. Scope of review: We summarize recent findings regarding the role of AMPK-mediated signaling pathways that are involved in: (1) metabolic reprogramming, (2) alteration of cellular redox status and antioxidant enzyme expression, (3) mitochondrial biogenesis, and (4) autophagy, a master regulator of mitochondrial quality control in skin fibroblasts from patients with mitochondrial diseases. Major conclusion: Induction of adaptive responses via AMPK-PFK2, AMPK-FOXO3a, AMPK-PGC-1α, and AMPK-mTOR signaling pathways, respectively is modulated for the survival of human cells under oxidative stress induced by mitochondrial dysfunction. We suggest that AMPK may be a potential target for the development of therapeutic agents for the treatment of mitochondrial diseases. General significance: Elucidation of the adaptive mechanism involved in AMPK activation cascades would lead us to gain a deeper insight into the crosstalk between mitochondria and the nucleus in affected tissue cells from patients with mitochondrial diseases. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.
    Full-text · Article · Oct 2013 · Biochimica et Biophysica Acta
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    • "Human brain has the highest consumption of glucose with respect to its size (60% of body’s resting state glucose) and the energy generated from glucose metabolism is essential to support synaptic transmission [15]; as a corollary, synaptic transmission is susceptible to the bioenergetic deficits associated with the progress of Alzheimer’s disease [16,17]. The insulin-stimulated brain glucose uptake knits and links brain insulin to synaptic transmission. "
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    ABSTRACT: Alzheimer's disease is a progressive neurodegenerative disease that entails impairments of memory, thinking and behavior and culminates into brain atrophy. Impaired glucose uptake (accumulating into energy deficits) and synaptic plasticity have been shown to be affected in the early stages of Alzheimer's disease. This study examines the ability of lipoic acid to increase brain glucose uptake and lead to improvements in synaptic plasticity on a triple transgenic mouse model of Alzheimer's disease (3xTg-AD) that shows progression of pathology as a function of age; two age groups: 6 months (young) and 12 months (old) were used in this study. 3xTg-AD mice fed 0.23% w/v lipoic acid in drinking water for 4 weeks showed an insulin mimetic effect that consisted of increased brain glucose uptake, activation of the insulin receptor substrate and of the PI3K/Akt signaling pathway. Lipoic acid supplementation led to important changes in synaptic function as shown by increased input/output (I/O) and long term potentiation (LTP) (measured by electrophysiology). Lipoic acid was more effective in stimulating an insulin-like effect and reversing the impaired synaptic plasticity in the old mice, wherein the impairment of insulin signaling and synaptic plasticity was more pronounced than those in young mice.
    Full-text · Article · Jul 2013 · PLoS ONE
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    • "In light of the recent report that the G6PD activity can be regulated by reversible tyrosine phosphorylation [49], whether AMPK can activate the G6PD by post-translational modification to increase NADPH production is worthy of further investigation. Although glycolysis and PPP are parallel pathways in glucose metabolism , the redistribution of glycolytic flux can regulate the PPP activity for the generation of NADPH [21] [22]. The findings of this study further suggest that the increase of glycolytic flux exerted by AMPK activation can regulate the intracellular NADPH production. "
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    ABSTRACT: We report that the energy metabolism shifts to anaerobic glycolysis as an adaptive response to oxidative stress in the primary cultures of skin fibroblasts from patients with MERRF syndrome. In order to unravel the molecular mechanism involved in the alteration of energy metabolism under oxidative stress, we treated normal human skin fibroblasts (CCD-966SK cells) with sub-lethal doses of H(2)O(2). The results showed that several glycolytic enzymes including hexokinase type II (HK II), lactate dehydrogenase (LDH) and glucose transporter 1 (GLUT1) were up-regulated in H(2)O(2)-treated normal skin fibroblasts. In addition, the glycolytic flux of skin fibroblasts was increased by H(2)O(2) in a dose-dependent manner through the activation of AMP-activated protein kinase (AMPK) and phosphorylation of its downstream target, phosphofructokinase 2 (PFK2). Moreover, we found that the AMPK-mediated increase of glycolytic flux by H(2)O(2) was accompanied by an increase of intracellular NADPH content. By treatment of the cells with glycolysis inhibitors, an AMPK inhibitor or genetic knockdown of AMPK, respectively, the H(2)O(2)-induced increase of NADPH was abrogated leading to the overproduction of intracellular ROS and cell death. Significantly, we showed that phosphorylation levels of AMPK and glycolysis were up-regulated to confer an advantage of survival for MERRF skin fibroblasts. Taken together, our findings suggest that the increased production of NADPH by AMPK-mediated increase of the glycolytic flux contributes to the adaptation of MERRF skin fibroblasts and H(2)O(2)-treated normal skin fibroblasts to oxidative stress.
    Full-text · Article · Feb 2012 · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
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