Regional brain metabolism with cytochrome c oxidase histochemistry in a PS1/A246E mouse model of autosomal dominant Alzheimer's disease: Correlations with behavior and oxidative stress
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Abstract
Mitochondrial dysfunction and brain metabolic alteration are early neurofunctional
aspects in Alzheimer's disease (AD). Regional brain metabolism was analyzed by cytochrome
c oxidase (COX) histochemistry in PS1-A246E mouse mutants, a model of autosomal dominant
AD overexpressing beta-amyloid (Abeta) peptide without amyloidosis or cell degeneration.
Immunohistochemical samples were analyzed on adjacent sections for regional Abeta1-42
levels, as well as DNA oxidative damage with 8-hydroxy-2-deoxyguanosine (8-OHdG).
COX activity increased in the basal forebrain nuclear complex, specific parts of the
amygdala and hippocampus, as well as in striatum and connected regions. On the contrary,
a hypometabolism was observed in midline thalamic, interpeduncular, and pedonculopontine
nuclei. The integration of these regions in circuitries subserving emotions, arousal,
and cognitive functions may explain why neurochemical alterations in specific brain
regions were linearly correlated with psychomotor slowing and disinhibition previously
reported in the mutant. As the PS1-A246E model appears to mimick prodromal AD, the
results support the existence of mitochondrial abnormalities prior to AD-related cognitive
deficits. However, since affected PS1-A246E brain regions were not primarily those
altered in AD-associated histopathological features and did not systematically display
either Abeta overexpression or higher 8-OHdG immunolabelling, the hypermetabolism
observed seems to comprise a compensatory reaction to early mitochondrial abnormalities;
furthermore, neuronal synaptic function should be considered as particularly relevant
in COX activity changes.