Potential Mechanism Underlying Exercise Upregulated Circulating Blood Exosome miR-215-5p to Prevent Necroptosis of Neuronal Cells and a Model for Early Diagnosis of Alzheimer's Disease.

Abstract

Exercise is crucial for preventing Alzheimer’s disease (AD), although the exact underlying mechanism remains unclear. The construction of an accurate AD risk prediction model is beneficial as it can provide a theoretical basis for preventive exercise prescription. In recent years, necroptosis has been confirmed as an important manifestation of AD, and exercise is known to inhibit necroptosis of neuronal cells. In this study, we extracted 67 necroptosis-related genes and 32 necroptosis-related lncRNAs and screened for key predictive AD risk genes through a random forest analysis. Based on the neural network Prediction model, we constructed a new logistic regression-based AD risk prediction model in order to provide a visual basis for the formulation of exercise prescription. The prediction model had an area under the curve (AUC) value of 0.979, indicative of strong predictive power and a robust clinical application prospect. In the exercise group, the expression of exosomal miR-215-5p was found to be upregulated; miR-215-5p could potentially inhibit the expressions of IDH1, BCL2L11, and SIRT1. The single-cell SCENIC assay was used to identify key transcriptional regulators in skeletal muscle. Among them, CEBPB and GATA6 were identified as putative transcriptional regulators of miR-215. After “skeletal muscle removal of load,” the expressions of CEBPB and GATA6 increased substantially, which in turn led to the elevation of miR-215 expression, thereby suggesting a putative mechanism for negative feedback regulation of exosomal homeostasis.