Exercise Modifies the Transcriptional Regulatory Features of Monocytes in Alzheimer’s Patients: A Multi-Omics Integration Analysis Based on Single Cell Technology

Abstract

Monocytes have been reported to be important mediators of the protective effect of exercise against the development of Alzheimer’s disease (AD). This study aims explored the mechanism by which monocytes achieve this. Using single cell transcriptome analysis, results showed that CD14 + and CD16 + monocytes interacted with other cells in the circulating blood. TNF, CCR1, APP, and AREG, the key ligand-receptor-related genes, were found to be differentially expressed between exercise-treated and AD patients. The SCENIC analysis was performed to identify individual clusters of the key transcription factors (TFs). Nine clusters (M1-M9) were obtained from the co-expression network. Among the identified TFs, MAFB, HES4, and FOSL1 were found to be differentially expressed in AD. Moreover, the M4 cluster to which MAFB, HES4, and FOSL1 belonged was defined as the signature cluster for AD phenotype. Differential analysis by bulkRNA-seq revealed that the expression of TNF, CCR1, and APP were all upregulated after exercise (p < 0.05). And ATF3, MAFB, HES4, and KLF4 that were identified in M4 clusters may be the TFs that regulate TNF, CCR1, and APP in exercise prescription. After that, APP, CCR1, TNF, ATF3, KLF4, HES4, and MAFB formed a regulatory network in the ERADMT gene set, and all of them were mechanistically linked. The ERADMT gene set has been found to be a potential risk marker for the development of AD and can be used as an indicator of compliance to exercise therapy in AD patients. Using single-cell integration analysis, a network of exercise-regulating TFs in monocytes was constructed for AD disease. The constructed network reveals the mechanism by which exercise regulated monocytes to confer therapeutic benefits against AD and its complications. However, this study, as a bioinformatic research, requires further experimental validation.