Brain Metabolism in Animal Models of Aspects of Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is accompanied by regional reductions in the metabolism of glucose, which begins decades before symptoms appear. AD appears to involve a wide range of alterations in mitochondrial function, such as changes in the activity of key mitochondrial enzymes. The close relationship between the TCA cycle and metabolism of the amino acid neurotransmitters glutamate and GABA renders the possibility that reduced cerebral glucose metabolism and mitochondrial dysfunction in AD is accompanied by changes in neurotransmitter homeostasis and glial-neuronal interactions. Therefore, the aim of the work in this thesis was to elucidate the metabolic consequences of different known pathological and pathophysiological aspects of AD and dementia on brain metabolism, with particular focus on their effect on glucose metabolism, neurotransmitter homeostasis and glial-neuronal interactions. Brain metabolism was investigated in DLST +/- mice with reduced activity of the α-ketoglutarate dehydrogenase complex (KGDHC; paper 1), in pR5 mice with tau hyperphosphorylation (paper 3), and in McGill-R-Thy1-APP rats with amyloid β (Aβ) pathology (papers 2 and 4). In papers 1, 3 and 4, animals were injected with 13C-labeled precursors, and brain extracts were analysed using 1H- and 13C nuclear magnetic resonance spectroscopy, high-performance liquid chromatography and gas chromatography – mass spectrometry (the latter was used in papers 1 and 3 only). In paper 2, in vivo 1H magnetic resonance spectroscopy was used to longitudinally investigate the metabolite content of brain regions in the McGill-R-Thy1-APP rat model with Aβ pathology. In paper 1, we found that decreased activity of KGDHC could lead to reduced glucose utilization in cortex, but diminished KGDHC activity did not affect neurotransmitter metabolism in any of the brain regions investigated. In paper 2, we demonstrated that an altered metabolic profile is evident prior to the appearance of Aβ plaques in a transgenic rat model of AD, and that the metabolite content of the dorsal hippocampus and the frontal cortex differs from that of controls at every age investigated during the progression of Aβ pathology. In paper 3, we found that mice with hyperphosphorylated tau protein had different metabolic states in the cortex and hippocampus. Glutamate metabolism was impaired in the hippocampus of pR5 mice. In the cortex, reduced concentration of [1-13C]glucose indicated increased glucose utilization, accompanied by increased turnover of glutamate, glutamine and GABA in pR5 mice. This suggested that cortical glutamatergic and GABAergic neurons as well as astrocytes were in a hypermetabolic state. In addition, a relative increase in the production of glutamate via pyruvate carboxylation was found. In paper 4, we demonstrated that both neuronal and astrocytic mitochondrial metabolism was compromised in several brain regions of 15-months-old rats with Aβ pathology. In particular, reduced turnover of amino acids derived from the TCA cycle, consistent with impaired TCA cycle flux, was found for glutamatergic and GABAergic neurons in the hippocampal formation and frontal cortex, and for astrocytes in the frontal cortex. Moreover, reduced de novo formation of amino acids via pyruvate carboxylation affected the synthesis of amino acids in the hippocampal formation and the retrosplenial/cingulate cortex. Also, indications of compromised transfer of glutamine between astrocytes and neurons were found. The results in paper 3 and 4 also demonstrated that glutamate homeostasis is compromised prior to aggregation of neurofibrillary tangles and Aβ plaque deposition. Exploring how different aspects of AD affect brain metabolism is essential to gain knowledge about the disease, and will provide a better foundation for development of new treatments and discovery of biomarkers to aid earlier diagnosis. Altogether, the studies in this thesis provide new knowledge about metabolic alterations in the brain of mice and rats recapitulating different aspects of AD.