Alzheimer’s disease (AD) has devastating consequences for patients during its slow, progressive course. It is important to understand the pathology of AD onset. Recently, circular RNAs (circRNAs) have been found to participate in many human diseases including cancers and neurodegenerative conditions. In this study, we mined the published dataset on the AMP-AD Knowledge Portal from the Mount Sinai Brain Bank (MSBB) to describe the circRNA profiles at different AD stages in brain samples from four brain regions: anterior prefrontal cortex, superior temporal lobe, parahippocampal gyrus and inferior frontal gyrus. In total, we found 147 circRNAs to be differentially expressed (DE) for different AD severity levels in the four regions. We also characterized the mRNA-circRNA co-expression network and annotated the potential function of circRNAs based on the co-expressed modules. Based on our results, we found that the most circRNA-regulated region in AD patients with severe symptoms was the parahippocampal gyrus. The strongest negatively AD severity-correlated module in the parahippocampal gyrus was enriched in cognitive disability and pathological-associated pathways such as synapse organization and regulation of membrane potential. Finally, a regression model based on the expression pattern of DE circRNAs in the module could help to distinguish the disease severity of patients, further supporting a role for circRNAs in AD pathology. In conclusion, our findings indicate that circRNAs in parahippocampal gyrus are possible biomarkers and regulators of AD as well as potential therapeutic targets.

Remote ischemic conditioning (RIC) is a procedure that can attenuate ischemic-reperfusion injury by conducting brief cycles of ischemia and reperfusion in the arm or leg. Extracellular vesicles (EVs) circulating in the bloodstream can release their content into recipient cells to confer protective function on ischemia-reperfusion injured (IRI) organs. Skeletal muscle cells are potential candidates to release EVs as a protective signal during RIC. In this study, we used C2C12 cells as a model system and performed cyclic hypoxia-reoxygenation (HR) to mimic RIC. EVs were collected and subjected to small RNA profiling and proteomics. HR induced a distinct shift in the miRNA profile and protein content in EVs. HR EV treatment restored cell viability, dampened inflammation, and enhanced tube formation in in vitro assays. In vivo, HR EVs showed increased accumulation in the ischemic brain compared to EVs secreted from normoxic culture (N EVs) in a mouse undergoing transient middle cerebral artery occlusion (tMCAO). We conclude that HR conditioning changes the miRNA and protein profile in EVs released by C2C12 cells and enhances the protective signal in the EVs to recipient cells in vitro.

27Alzheimer's Disease (AD) has devastating consequences for patients during its slow, progressive 28 course. It is important to understand the pathology of AD onset. Recently, circular RNAs 29 (circRNAs) have been found to participate in many human diseases including cancers and 30 neurodegenerative conditions. In this study, we mined the published dataset on the AMP-AD 31 Knowledge Portal from the Mount Sinai Brain Bank (MSBB) to describe the circRNA profiles at 32 different AD stage in brain samples from four AD patients brain regions, anterior prefrontal cortex, 33 superior temporal lobe, parahippocampal gyrus, and inferior frontal gyrus. We found in total 147 34 circRNAs to be differentially expressed (DE) during AD progression in the four regions. We also 35 characterized the mRNA-circRNA co-expression network and annotated the potential function of 36 circRNAs based on the co-expressed modules. Based on our results, we propose that 37 parahippocampal gyrus is the most circRNA-regulated region during the AD progression. The 38 strongest negatively AD stage-correlated module in parahippocampal gyrus were enriched in 39 cognitive disability and pathological-associated pathways such as synapse organization and 40 regulation of membrane potential. Finally, the regression model based on the expression pattern of 41 DE circRNAs in the module could help to distinguish the disease severity of patients, further 42 supported the importance of circRNAs in AD pathology. In conclusion, our finding indicates that 43 circRNAs in parahippocampal gyrus are possible regulators of AD progression and potentially be a 44 therapeutic target or of AD. 45 46 47 48 3