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.
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.
Strazielle
Catherine
C
Inserm, U954, Faculty of Medicine, Vandoeuvre les Nancy, 54500, France. straziel@persmail.uhp-nancy.fr
Jazi
Rozat
R
Verdier
Yann
Y
Qian
Sue
S
Lalonde
Robert
R
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001481:Basal Metabolism / Q000235:genetics; D001522:Behavior, Animal / Q000502:physiology*; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics; D025063:Chromosome Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004249:DNA Damage / Q000235:genetics; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000032:analysis / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006651:Histocytochemistry / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D011597:Psychomotor Performance / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D003576:Electron Transport Complex IV