| dc.description.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. | nb_NO |
