Abstract
BackgroundOxidative stress (OS) is an important factor in brain aging and neurodegenerative diseases. Certain neurons in different brain regions exhibit selective vulnerability to OS. Currently little is known about the underlying mechanisms of this selective neuronal vulnerability. The purpose of this study was to identify endogenous factors that predispose vulnerable neurons to OS by employing genomic and biochemical approaches.ResultsIn this report, using in vitro neuronal cultures, ex vivo organotypic brain slice cultures and acute brain slice preparations, we established that cerebellar granule (CbG) and hippocampal CA1 neurons were significantly more sensitive to OS (induced by paraquat) than cerebral cortical and hippocampal CA3 neurons. To probe for intrinsic differences between in vivo vulnerable (CA1 and CbG) and resistant (CA3 and cerebral cortex) neurons under basal conditions, these neurons were collected by laser capture microdissection from freshly excised brain sections (no OS treatment), and then subjected to oligonucleotide microarray analysis. GeneChip-based transcriptomic analyses revealed that vulnerable neurons had higher expression of genes related to stress and immune response, and lower expression of energy generation and signal transduction genes in comparison with resistant neurons. Subsequent targeted biochemical analyses confirmed the lower energy levels (in the form of ATP) in primary CbG neurons compared with cortical neurons.ConclusionLow energy reserves and high intrinsic stress levels are two underlying factors for neuronal selective vulnerability to OS. These mechanisms can be targeted in the future for the protection of vulnerable neurons.
Highlights
Oxidative stress (OS) is an important factor in brain aging and neurodegenerative diseases
In initial studies described in this paper, we found that cerebellar granule (CbG) cells were a group of cells that were quite vulnerable to OS, whereas neurons from the cerebral cortex were relatively resistant
Despite the caveat that studies performed with neurons grown in vitro may not reflect exactly the responses of neurons in vivo, primary neuronal cultures were used in these studies because they are composed of approximately 90–95% neurons
Summary
Oxidative stress (OS) is an important factor in brain aging and neurodegenerative diseases. In order to shed more light on SNV in general, transcriptomic analyses of neurons that exhibit differential vulnerability to various insults or to the damage brought about by neurological diseases have been performed in human and rodent hippocampus and human midbrain dopaminergic neurons [14,15,16,17,18,19]. None of these studies except for the one on dopaminergic neurons focused on a specific form of stress, or on genes or bio-functions that might contribute to the etiology of SNV
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