Ologies.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptJournal of Cerebral Blood Flow

Ologies.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Journal of Cerebral Blood Flow Metabolism (2014) 34, 90614 2014 ISCBFM All rights reserved 0271-678X/14 32.00 jcbfmORIGINAL ARTICLENeuronal and astrocytic metabolism in a transgenic rat model of Alzheimer’s diseaseLinn Hege Nilsen1, Menno P Witter2 and Ursula Sonnewald1 Regional hypometabolism of glucose within the brain is a hallmark of Alzheimer’s disease (AD). Having said that, little is known regarding the particular alterations of neuronal and astrocytic metabolism involved in homeostasis of glutamate and GABA in AD. Right here, we investigated the effects of amyloid b (Ab) pathology on neuronal and astrocytic metabolism and Sigma 1 Receptor Modulator supplier glial-neuronal interactions in amino acid neurotransmitter homeostasis inside the transgenic McGill-R-Thy1-APP rat model of AD compared with healthful controls at age 15 months. Rats have been injected with [1-13C]glucose and [1,2-13C]acetate, and extracts from the hippocampal formation as well as many cortical regions had been analyzed working with 1H- and 13C nuclear magnetic resonance spectroscopy and high-performance liquid chromatography. Reduced tricarboxylic acid cycle turnover was evident for glutamatergic and GABAergic neurons in hippocampal formation and frontal S1PR2 Antagonist MedChemExpress cortex, and for astrocytes in frontal cortex. Pyruvate carboxylation, which can be required for de novo synthesis of amino acids, was decreased and impacted the degree of glutamine in hippocampal formation and these of glutamate, glutamine, GABA, and aspartate inside the retrosplenial/cingulate cortex. Metabolic alterations were also detected inside the entorhinal cortex. General, perturbations in energy- and neurotransmitter homeostasis, mitochondrial astrocytic and neuronal metabolism, and aspects in the glutamate lutamine cycle had been discovered in McGill-R-Thy1-APP rats. Journal of Cerebral Blood Flow Metabolism (2014) 34, 90614; doi:10.1038/jcbfm.2014.37; published online 5 March 2014 Search phrases: dementia; GABA; glutamate; neurotransmitters; MR spectroscopyINTRODUCTION Regional hypometabolism of glucose in the brain is usually a hallmark of Alzheimer’s disease (AD). Compromised mitochondrial function and bioenergetics in AD have also been reported, and among essentially the most robust findings are diminished activity of a number of enzymes involved in oxidative metabolism of glucose: the pyruvate dehydrogenase (PDH) complicated,1,2 the a-ketoglutarate dehydrogenase complicated,1,two and cytochrome c oxidase/complex IV in the electron transport chain.3 Because the tricarboxylic acid (TCA) cycle intermediate a-ketoglutarate (a-KG) may be the precursor for glutamate and subsequently for GABA in GABAergic neurons and glutamine in astrocytes, the metabolism of glucose and amino-acid neurotransmitters in the brain is closely linked. The homeostasis of glutamate and GABA also needs glial euronal interactions, because the transporters and enzymes involved in uptake, synthesis, and degradation of these neurotransmitters are differentially distributed in neurons and astrocytes. As a result, diseases that encompass alterations to glucose metabolism could involve alterations in cellular power metabolism, amino-acid neurotransmitter homeostasis, and glial euronal interactions. Indeed, decreased brain glutamate levels in patients with AD point toward impairment of neurotransmitter homeostasis within the disease.4 Final results from 13C nuclear magnetic resonance (NMR) spectroscopy studies in AD individuals and in brain extracts from APP-PS1 mice have shown reduced oxidative metabolism of g.