Circadian clock-mediated neuronal gene expression in Aß toxicity and excitotoxicity

In recent decades, transcriptome analysis has been widely used to understand human disease pathogenesis and identify therapeutic targets and biomarkers. Accumulated reports in patients with neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, have also provided evidence of dysregulated gene expression related to neuropathogenesis. However, obtaining samples from neurodegenerative patients is more challenging than other human diseases due to low accessibility. Also, brain tissues and cerebrospinal fluid are composed of multiple cell types, so they are unsuitable for obtaining neural cell-type-specific gene expression profiles. Thus, we here report gene expression profiles in primary neuronal cultures exposed to Aß toxicity and glutamate excitotoxicity to understand pathological gene expression in neurons. By RNA-sequencing analysis, we compare transcriptomes and find that two groups of genes show similar expression patterns in Aß toxicity excitotoxicity—they are either up- or down-regulated in both conditions. Genes in the two groups are related to synaptic function and cell signaling, which are well-known biological functions altered in Aß toxicity and excitotoxicity. Interestingly, the analysis reveals a possibility that circadian clock (molecular oscillator generating daily rhythms)-related genes are dysregulated in both conditions. We confirm the reduced circadian transcription factor Bmal1 levels in Aß toxicity and glutamate excitotoxicity. RNA-sequencing analysis in Bmal1-deleted neurons shows potential relationships between BMAL1 and synaptic functions. Thus, this transcriptome study provides evidence of the potential roles of the circadian clock in neuropathogenesis. Overall design: Transcriptomes in two neuropathological conditions, Aß toxicity and glutamate excitotoxicity, were examined. Total RNAs were extracted in primary neuronal cultures and subjected to RNA-sequencing analysis to understand neuron-specific gene expression profiles. Then, similar experiments were performed in neurons cultured from the circadian transcription factor Bmal1-deleted mice. We compared transcriptomes between the samples to understand their relationships.