Comparative physiological and transcriptomic analyses reveal key regulatory networks and potential hub genes controlling peanut chilling tolerance.

The unclear molecular mechanism by which peanuts adapt to chilling stress limits progress in molecular breeding for peanut chilling tolerance. Here, the physiological and transcriptional differences between two genotypes with contrasting tolerance under chilling stress were compared. The inhibition of photosynthesis mainly caused by stomatal factors was a common response of peanut seedlings to chilling stress. Chilling-tolerant genotypes could inhibit the accumulation of ROS to adapt to chilling stress, and enhanced activities of CAT and APX were major causes of lower H2O2 content. The results of a conjoint analysis of physiological indices and the RNA-Seq database by WGCNA indicated that the genes in key modules were significantly enriched in pathways related to the oxidation-reduction process. Hub genes encoding RLK, CAT, MYC4, AOS, GST, PP2C, UPL5 and ZFP8 were likely to positively regulate peanut chilling tolerance, but hub genes encoding PAO, NAC2 and NAC72 were likely to negatively regulate peanut chilling tolerance.

Long-Term High-Fat Diet Impairs AQP4-Mediated Glymphatic Clearance of Amyloid Beta.

As a risk factor for Alzheimer's disease (AD), studies have demonstrated that long-term high-fat diet (HFD) could accelerate the deposition of amyloid beta (Aß) in the brain. The glymphatic system plays a critical role in Aß clearance from the brain. However, studies investigating the effects of long-term HFD on glymphatic function have reported paradoxical outcomes, and whether glymphatic dysfunction is involved in the disturbance of Aß clearance in long-term HFD-fed mice has not been determined. In the present study, we injected fluorescently labeled Aß into the hippocampus and found that Aß clearance was decreased in HFD-fed mice. We found that long-term HFD-fed mice had decreased glymphatic function by injecting fluorescent tracers into the cisterna magna and corpus striatum. In long-term HFD-fed mice, aquaporin-4 (AQP4) polarization in the cortex was disrupted, and glymphatic clearance activity was positively correlated with the AQP4 polarization index. In HFD-fed mice, the disturbance of Aß clearance from the hippocampus was exacerbated by TGN-020, a specific inhibitor of AQP4, whereas TGN-073, an enhancer of AQP4, ameliorated it. These findings suggest that long-term HFD disrupts Aß clearance by inhibiting AQP4-mediated glymphatic function. The underlying mechanism may involve the disruption of AQP4 polarization.

AQP4 Endocytosis-Lysosome Degradation Mediated by MMP-9/ß-DG Involved in Diabetes Cognitive Impairment.

Cognitive impairment is considered to be one of the important comorbidities of diabetes, but the underlying mechanisms are widely unknown. Aquaporin-4 (AQP4) is the most abundant water channel in the central nervous system, which plays a neuroprotective role in various neurological diseases by maintaining the function of glymphatic system and synaptic plasticity. However, whether AQP4 is involved in diabetes-related cognitive impairment remains unknown. ß-dystroglycan (ß-DG), a key molecule for anchoring AQP4 on the plasma membrane of astrocytes and avoiding its targeting to lysosomes for degradation, can be cleaved by matrix metalloproteinase-9 (MMP-9). ß-DG deficiency can cause a decline in AQP4 via regulating its endocytosis. However, whether cleavage of ß-DG can affect the expression of AQP4 remains unreported. In this study, we observed that diabetes mice displayed cognitive disorder accompanied by reduction of AQP4 in prefrontal cortex. And we found that bafilomycin A1, a widely used lysosome inhibitor, could reverse the downregulation of AQP4 in diabetes, further demonstrating that the reduction of AQP4 in diabetes is a result of more endocytosis-lysosome degradation. In further experiments, we found diabetes caused the excessive activation of MMP-9/ß-DG which leaded to the loss of connection between AQP4 and ß-DG, further inducing the endocytosis of AQP4. Moreover, inhibition of MMP-9/ß-DG restored the endocytosis-lysosome degradation of AQP4 and partially alleviated cognitive dysfunction in diabetes. Our study sheds new light on the role of AQP4 in diabetes-associated cognitive disorder. And we provide a promising therapeutic target to reverse the endocytosis-lysosome degradation of AQP4 in diabetes, such as MMP-9/ß-DG.