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Expression data from Cerebral Cortex or Hippocampus of COX-1 or COX-2 null mice

ABSTRACT: To further understand the physiological role of cyclooxygenase (COX), the critical enzyme involved in the production of eicosanoids from arachidonic acid, we performed microarray analysis of gene expression in the cerebral cortex and hippocampus of mice deficient in COX-1 (COX-1-/-) or COX-2 (COX-2-/-). Expression of lipid (ATP citrate lyase, acetyl-CoA acetyltransferase, hydroxyacyl-CoA dehydrogenase) and homocysteine (methionine adenosyltransferase, S-adenosylhomocysteine hydrolase) metabolism genes was increased in the cerebral cortex of COX-2 -/- mice. Further, expression of GABAergic neurotransmission genes (GABA transporter 3, GABA-A receptor subunit ?1) was altered in the cerebral cortex and hippocampus of COX-2 -/- mice. A COX isoform specific effect was observed in the expression of Janus Kinase (JAK) 1 and 2. COX-1 -/- mice exhibited an increase in JAK1 expression while COX-2 -/- mice exhibited a decrease in JAK2 expression, an observation consistent with a previously demonstrated COX isoform specific effect on the expression of NF-kB. In summary, this study demonstrates the wide ranging effects of genetic deletion of COX isoforms in the mouse brain and suggests that inhibition of COX activity may alter the profile of gene expression in specific areas of the brain. We used nylon cDNA microarrays to detail the global programme of gene expression in the Cerebral Cortex and Hippocampus of COX-1 and COX-2 null (knockout) mice Keywords: brain, cerebral cortex, hippocampus, COX-1 WT, COX-1 KO, COX-2 WT, COX-2 KO and COX-2 heterozygous

ORGANISM(S): Mus musculus

PROVIDER: GSE5342 | GEO | 2007/02/05

SECONDARY ACCESSION(S): PRJNA96197

REPOSITORIES: GEO

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Project description:Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes in brain energy metabolism arise in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology. Neurons and astrocytes function in close metabolic collaboration, which is essential for the recycling of neurotransmitters in the synapse. However, how this metabolic interplay may be affected during the early stages of AD development has not been sufficiently investigated. Here, we provide an integrative analysis of cellular metabolism during the early stages of Aβ accumulation in the cerebral cortex and hippocampus of the 5xFAD mouse model of AD. Our electrophysiological examination revealed an increase in spontaneous excitatory signaling in hippocampal brain slices of 5xFAD mice. This hyperactive neuronal phenotype coincided with decreased hippocampal TCA cycle metabolism mapped by stable 13C isotope tracing. Particularly, reduced astrocyte TCA cycle activity led to decreased glutamine synthesis, in turn hampering neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, cerebral cortical slices of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism suggesting a metabolic compensation. When we explored the brain proteome and metabolome of the 5xFAD mice, we found limited changes, supporting that the functional metabolic disturbances between neurons and astrocytes are early events in AD pathology. In addition, we show that synaptic mitochondrial and glycolytic function was impaired selectively in the 5xFAD hippocampus, whereas non-synaptic mitochondrial function was maintained. These findings were supported by ultrastructural analyses demonstrating disruptions in mitochondrial morphology, particularly in the 5xFAD hippocampus. Collectively, our study reveals complex region and cell specific metabolic adaptations, in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunction in AD.

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Expression data from Cerebral Cortex or Hippocampus of COX-1 or COX-2 null mice

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