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 inside a transgenic rat model of Alzheimer’s diseaseLinn Hege Nilsen1, Menno P Witter2 and Ursula Sonnewald1 Regional hypometabolism of RGS8 Inhibitor site glucose within the brain is a hallmark of Alzheimer’s Mite Inhibitor list illness (AD). On the other hand, tiny is known in regards to the certain 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 glial-neuronal interactions in amino acid neurotransmitter homeostasis in the transgenic McGill-R-Thy1-APP rat model of AD compared with wholesome controls at age 15 months. Rats had been injected with [1-13C]glucose and [1,2-13C]acetate, and extracts on the hippocampal formation too as quite a few cortical regions had been analyzed making use of 1H- and 13C nuclear magnetic resonance spectroscopy and high-performance liquid chromatography. Decreased tricarboxylic acid cycle turnover was evident for glutamatergic and GABAergic neurons in hippocampal formation and frontal cortex, and for astrocytes in frontal cortex. Pyruvate carboxylation, which can be needed for de novo synthesis of amino acids, was decreased and affected the degree of glutamine in hippocampal formation and these of glutamate, glutamine, GABA, and aspartate in the retrosplenial/cingulate cortex. Metabolic alterations had been also detected within the entorhinal cortex. Overall, perturbations in energy- and neurotransmitter homeostasis, mitochondrial astrocytic and neuronal metabolism, and elements of the glutamate lutamine cycle were found in McGill-R-Thy1-APP rats. Journal of Cerebral Blood Flow Metabolism (2014) 34, 90614; doi:10.1038/jcbfm.2014.37; published on line five March 2014 Keyword phrases: dementia; GABA; glutamate; neurotransmitters; MR spectroscopyINTRODUCTION Regional hypometabolism of glucose within the brain is often a hallmark of Alzheimer’s illness (AD). Compromised mitochondrial function and bioenergetics in AD have also been reported, and among the most robust findings are diminished activity of several 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 from the electron transport chain.three Since 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 inside the brain is closely linked. The homeostasis of glutamate and GABA also requires glial euronal interactions, since the transporters and enzymes involved in uptake, synthesis, and degradation of these neurotransmitters are differentially distributed in neurons and astrocytes. Hence, diseases that encompass alterations to glucose metabolism may possibly involve alterations in cellular energy metabolism, amino-acid neurotransmitter homeostasis, and glial euronal interactions. Certainly, decreased brain glutamate levels in patients with AD point toward impairment of neurotransmitter homeostasis inside the disease.four Benefits from 13C nuclear magnetic resonance (NMR) spectroscopy studies in AD sufferers and in brain extracts from APP-PS1 mice have shown reduced oxidative metabolism of g.
