ABSTRACT
Disrupted circadian rhythms are associated with the onset of chronic diseases and impairments, including cancer, diabetes, and hypertension. However, whether circadian disruptions accelerate the progression of Alzheimer's disease and the respective pathway remains unclear. In this study, we constructed animal models using male C57BL/6N and APP/PS1 mice. Irregular illumination during sleeping hours was administered to the mice in our intervention groups to consistently disrupt their circadian rhythms. The impact of the intervention was evaluated through body weight tracking, cerebral index determination, histopathological staining, and biochemical marker analysis. Transcriptomic sequencing identified critical genes, with the data subsequently validated using RNA m6A detection and site analysis. The evaluations revealed that circadian disruptions impaired normal weight gain, liver and kidney functions, neuronal cells, and overall brain function. Transcriptomic sequencing data revealed a trend of elevating expression of Hif3α mRNA in the intervention groups. Further analysis of specific gene sites revealed that m6A methylation of the Hif3α gene at m6A site 3632 primarily drove the observed variations in HIF3A protein expression in our model. Furthermore, the expression of proteins in PC12 cells, N2a cells, and mice brains validated that an increase in HIF3A expression decreased KDM3A and TGF-ß1 protein expression. Our study reveals a hitherto unknown pathway through which the disruption of circadian rhythms, by triggering m6A methylation at m6A site 3632 in the Hif3α gene, leads to the initiation and acceleration of AD. These findings provide valuable insights and guidelines for treating AD patients and enhancing caregiving by professionals.
ABSTRACT
The development of new drug therapies for Alzheimer's disease (AD) is an important research topic today, but the pathogenesis of AD has not been thoroughly studied, and there are still several shortcomings in existing drug therapies. Therefore, this study aims to explore the molecular mechanism of lactoferrin in the treatments of AD and ulcerative colitis (UC) which are susceptible to AD, starting from the principle of "one drug, two diseases, and the same treatment." This study used pathological staining and specific indicators staining to preliminarily evaluate the interventions of lactoferrin on UC injury and AD progression. And 16s RNA full-length sequencing was used to investigate the effect of lactoferrin on the abundance of intestinal microbiota in AD mice. Then, intestinal tissue and brain tissue metabolomics analysis were used to screen specific metabolic pathways and preliminarily verify the metabolic mechanism of lactoferrin in alleviating 2 diseases by regulating certain specific metabolites. Moreover, lactoferrin significantly changed the types and abundance of gut microbiota in AD mice complicated by UC. To conclude, this study proved the clinical phenomenon of AD susceptibility to UC, and verified the therapeutic effect of lactoferrin on 2 diseases. More importantly, we revealed the possible molecular mechanism of LF, not only does it enrich the cognitive level of lactoferrin in alleviating AD by regulating the gut microbiota through the brain gut axis from the perspective of the theory of "food nutrition promoting human health," but it also provides a practical basis for the subsequent research and development of lactoferrin and drug validation from the perspective of "drug food homology."
