Synaptosome RNA and bulk RNA sequencing of Alzheimer's disease and control mouse frontal cortex tissue

We measured RNA synaptic localization differences in human AD patient samples. We performed RNA sequencing to identify mislocalized coding and non-coding RNAs and contrasted findings with global expression differences in human frontal and temporal lobe tissue as well as an APP/PSEN1 AD mouse model. We discovered significant mRNA localization differences in AD tissue including upregulation of genes related to cell differentiation and adhesion, and downregulation of genes related to cellular component organization ion transport. In addition, we identified major differences among circular RNAs (circRNAs) localized to synapses. Among our data, we discovered two unique isoforms of circGSK3ß that are differentially expressed in AD. Furthermore, we found that expression of these distinct isoforms affects tau phosphorylation in neural cell culture. These discoveries substantiate the importance of circRNAs in the brain and in neurodegenerative disease. Identifying differences in synaptic-localized mRNAs and circRNAs opens new avenues to understanding AD synaptic pathology and identifying potential therapeutic targets. Overall design: Synaptosomes were prepared from mouse frontal cortex tissue homogenate including wild-type and the APP/PSEN1 transgenic Alzheimer's disease mouse model. Both isolated synaptosomes and bulk homogenate were RNA-sequenced.