| With socioeconomic development and population aging,it is urgent to initiate evaluation of nutritional function of the food and develop nutritional intervention,aiming on linking the dietary and health.Sesamol is the primary component from sesame seed,which is one of the major oil crops.It has superior antioxidant bioactivity and is widely utilized in food industry,pharmaceutical research,and daily chemical products development.It has been found that sesamol also possesses blood-brain barrier permeability and has potential neuroprotective effects.However,the effects of sesamol on aging and age-related neurodegenerative diseases and its underlying mechanism remain elusive.Here,the present study focused on investigating the effect of sesamol on cognitive deficits of the aging and AD model mice and determining the molecular mechanisms by food nutrition and molecular biology technologies.(1)To investigate the protective effects of sesamol on cognitive deficits and memory loss in male 12-month old CD-1 aging mice.The mice were fed with sesamol formula diet(0.1%w/w,100 mg/kg bodyweight)for 3 months.The cognition and memory assessment were evaluated by behavioral tests including water-maze test and Y-maze test.Dietary supplementation of sesamol alleviated age-related cognitive deficits and memory impairments.Histological study and transmission electron microscopy observation indicated that sesamol improved the neuronal damage and apoptosis triggered by aging,and restored the length and width of post-synaptic dense structure.Sesamol also enhanced the protein expression of PSD-95,a post-synaptic dense protein,which might be explained by sesamol improving the expression of brain-derived neurotrophic factor(BDNF)and reducing A?deposition.(2)To uncover the molecular mechanism of the neuroprotective effects of sesamol on cognitive dysfunction in aging mice,Western blots,q PCR and immunohistochemical techniques were employed in current study.It was revealed that sesamol could reduce the level of MDA,an oxidative damage marker,and improve the activity and expression of antioxidant enzymes such as CAT,SOD,HO-1 and NQO-1,in blood and brain of aging mice.These results might be related to sesamol activating the Nrf2/ARE antioxidant defense enzyme system;Further research found sesamol suppressed the neuroinflammatory and over-activation of microglia in the brain,which could be partly explained by the preventive effects of sesamol on NF?B pathway activation;Apo E is a key molecule in the brain to clear A?.We found that sesamol could activate Apo E-related signaling pathway,which suggested that the regulation of sesamol in brain lipid metabolism might be the key mechanism for improving cognitive impairment.Besides,since the intestinal biodistribution of sesamol is much higher than the content in the brain,the effects of sesamol on gut microecology were analyzed by 16S r DNA sequencing technology.It has been found that dietary supplementation of sesamol reshaped the gut microbiome and reduced the LPS level in the blood,which indicated that the gut-brain axis regulation could be another mechanism of the anti-inflammatory and antioxidant effects of sesamol on aging mice.(3)In order to further reveal the effect of sesamol on the cognitive deficits in AD,an aging-related neurodegenerative disease,the APPswe/PSEN1d E9 transgenic(hereinafter referred to as APP/PS1)AD model mice and Apo E-/-AD model mice were selected to perform experiments.Behavioral studies showed that sesamol significantly attenuated cognitive dysfunction in APP/PS1 mice,and significantly inhibited A?aggregation in the brain cortex and hippocampus;Moreover,we found that sesamol activated Apo E-related pathway and inactivated the neuroinflammation in APP/PS1 mice brain;However,sesamol could not improve the damage and anxiety-like behaviors of high-fat diet-fed Apo E-/-mice;Immunohistochemistry and other results suggested that sesamol could not completely improve the brain neuronal damage and synaptic ultrastructure changes,and inhibit the accumulation of A?in Apo E-/-mice brain compared with wildtype mice.Therefore,it was speculated that the neuroprotective effect of sesamol on AD might be closely related to the Apo E pathway.(4)To reveal the mediating role of ApoE played in improving the effects of sesamol on aging and AD cognitive dysfunction,further investigation was performed on Apo E-/-mouse model mentioned above.It was found that sesamol could activate the Apo E-related pathway gene expressions including LXR and LRP1,inhibit of hippocampal neuroinflammatory cytokines IL-1?and TNF-?expression,and up-regulate of BDNF expression in wild type but not in Apo E-/-mice;Moreover,to clarify the effects of sesamol on the"gut-brain axis"-mediated mechanism,GC and 16S r DNA sequencing were employed to analyze the changes of gut microbiota and microbial metabolites in Apo E-/-mice.It was found that sesamol significantly reshaped the microbiome of the wild-type mouse by increasing the abundance of microorganisms such as Lactococcus,and enhancing the production of microbial metabolites short-chain fatty acids including acetic acid,propionic acid and butyric acid,and suppressing the gut inflammation and the level of LPS in the blood.However,these beneficial effects were not significant in the Apo E-/-mice,which indicated that the Apo E-associated lipoprotein pathway played a pivotal and regulatory role in the neuroprotective effects of sesamol.In summary,sesamol could improve the cognitive deficits of aging and age-related neurodegenerative diseases and the underlying mechanisms were systemic,which including its anti-oxidant and anti-inflammatory effects,up-regulating the Apo E-associated lipid metabolism pathway,and mediating the"gut-brain axis".The present study could provide new strategies for nutritional intervention studies of natural functional food components on neuronal function,and provide a theoretical basis for the development of healthy foods with sesame as a major functional ingredient. |
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