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1H- and 13C-NMR spectroscopy of Thy-1-APPSL mice brain extracts indicates metabolic changes in Alzheimer’s disease

  • Neurology and Preclinical Neurological Studies - Original Article
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Abstract

Biochemical alterations underlying the symptoms and pathomechanisms of Alzheimer’s disease (AD) are not fully understood. However, alterations of glucose metabolism and mitochondrial dysfunction certainly play an important role. 1H- and 13C-NMR spectroscopy exhibits promising results in providing information about those alterations in vivo in patients and animals, especially regarding the mitochondrial tricarboxylic acid (TCA) cycle. Accordingly, transgenic mice expressing mutant human amyloid precursor protein (APPSL)—serving as a model of neuropathological changes in AD—were examined with in vitro 1D 1H- and 2D 1H-13C-HSQC-NMR spectroscopy after oral administration of 1-13C-glucose and acquisition of brain material after 30 min. Perchloric acid extracts were measured using a 500 MHz spectrometer, providing more detailed information compared to in vivo spectra achievable nowadays. Area under curve (AUC) data of metabolite peaks were obtained and normalized in relation to the creatine signal, serving as internal reference. Besides confirming well-known metabolic alterations in AD like decreased N-acetylaspartate (NAA)/Creatine (Cr) ratio, new findings such as a decrease in phosphorylcholine (PC) are presented. Glutamate (Glu) and glutamine (Gln) concentrations were decreased while γ-aminobutyric acid (GABA) was elevated in Thy1-APPSL mice. 13C-NMR spectroscopy revealed a shift in the Glx-2/Glx-4-ratio—where Glx represents a combined Glu/Gln-signal—towards Glx-2 in AD. These findings correlated well with the NAA/Cr-ratio. The Gln-4/Glu-4-ratio is altered in favor of Glu. Our findings suggest that glutamine synthetase (GS), which is predominantly present in glial cells may be impaired in the brain of Thy1-APPSL transgenic mice. Since GS is an ATP-dependent enzyme, mitochondrial dysfunction might contribute to reduced activity, which might also account for the increased metabolism of glutamate via the GABA shunt, a metabolic pathway to bypass intra-mitochondrial α-ketoglutarate-dehydrogenase, resulting in elevated GABA levels.

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Acknowledgments

We thank Claudia Jourdan, and Dr. Löhr for their excellent technical assistance.

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Authors and Affiliations

  1. Institute of Neuroradiology, Goethe-University Hospital, Frankfurt, Germany

    A. Doert, U. Pilatus & F. Zanella

  2. Department of Pharmacology, Campus Riedberg, University of Frankfurt, Biocenter N260 R1.09, Max-von-Laue Str. 9, Frankfurt, Germany

    W. E. Müller & G. P. Eckert

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  1. A. Doert
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Doert, A., Pilatus, U., Zanella, F. et al. 1H- and 13C-NMR spectroscopy of Thy-1-APPSL mice brain extracts indicates metabolic changes in Alzheimer’s disease. J Neural Transm 122, 541–550 (2015). https://doi.org/10.1007/s00702-015-1387-3

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