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Title: Modulation of energy homeostasis by amyloid precursor protein (APP)
Authors: CHUA LI MIN
Keywords: amyloid, Alzheimer's, APP, energy, glucose, insulin
Issue Date: 30-Mar-2011
Citation: CHUA LI MIN (2011-03-30). Modulation of energy homeostasis by amyloid precursor protein (APP). ScholarBank@NUS Repository.
Abstract: The amyloid precursor protein (APP) has been implicated in Alzheimer?s disease (AD) as it is cleaved by secretases to produce amyloid beta peptide (A?), which aggregates to form the extracellular amyloid plaques characteristic of AD pathology. In neurons, APP exists as 3 isoforms of different lengths comprising of 695 (APP695), 751 (APP751) and 770 (APP770) amino acid residues, with APP695 being the major isoform present. However in AD, upregulation of the Kunitz-protease inhibitor (KPI) domain containing APP751 isoform was found to correlate with amyloid plaque density. Therefore it was believed that both A? and APP751 might be associated with the biological changes in the diseased brain. Interestingly, recent evidence suggests that APP might regulate glucose and insulin levels. Further, APP has also been associated with the development of insulin resistance. However, these putative functions of APP have not been studied extensively in neuronal cells. Since glucose hypometabolism and insulin resistance are associated with AD, it is likely that different isoforms of APP might modulate energy homeostasis differentially in the brain through regulating glucose metabolism and insulin signaling. Moreover, A? deposition has also been previously found to precede glucose hypometabolism, suggesting that A? might affect glucose metabolism. In this study, the effects of APP695sw and APP751sw on energy metabolism were assessed by generating APP expressing stable cell lines from a novel APP deficient neuronal cell line. APP695sw was found to increase the intracellular glucose content, which was accompanied by high mitochondrial activity and subsequent increased ROS production and caspase-3 activation. Additionally, there was also decreased insulin signaling in the APP695sw cells compared to APP751sw cells. Conversely, APP751sw cells contained lower intracellular glucose levels and mitochondrial activity, thus reducing the generation of ROS and caspase-3 activation. Insulin signaling was also increased and restored in the APP751sw cell line. As reduced insulin signaling has been associated with increased tau phosphorylation, the higher level of insulin signaling associated with APP751sw as compared to APP695sw implies that the expression of APP751 in neurons might be beneficial in AD since it would reduce the amount of tau phosphorylation and oxidative stress. The effects of an increasing A? production on glucose metabolism were also examined using APPsw/PS1deltaE9 mice that produce increasing A? with aging. A differential effect of A? on glucose metabolism was found. Specifically, a decline in the metabolic rate of glucose (CMRglc), marked by high brain glucose levels was detected at low concentrations of A?. When A? concentrations increased, a marked reduction in brain glucose content was observed instead, together with low brain insulin and glucose transporter (GLUT-4) levels. This differential effect of A? on glucose metabolism probably explains why certain imaging studies have not managed to find a good correlation between A? and CMRglc; since there is the possible confounding factor of impaired glucose uptake that occurs with elevated A? production.
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