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

Nilsen, Linn Hege
Doctoral thesis
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URI
http://hdl.handle.net/11250/2372769
Date
2015
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  • Institutt for nevromedisin og bevegelsesvitenskap [3579]
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.
Publisher
NTNU
Series
Doctoral thesis at NTNU;2015:298

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