Altered Non‐Coding RNA‐Histone Acetylation Regulatory Circuit Is Associated With Cognitive Impairment via Gut Dysbiosis in Aging Mice

Abstract

Advancing age is the top risk factor for the development of neurodegenerative disorders such as Alzheimer's Disease (AD). However, the contribution of the aging process to Alzheimer's disease (AD) pathology remain unclear. It is also unclear, whether age‐related disruption of the gut‐barrier integrity or dysbiosis causes impaired hippocampal memory. Allyl sulfide (AS), an organic sulfur compound in garlic, has many health benefits and is known for its detoxifying agents. However, the precise role of allyl sulfide in regulating hippocampal memory function at mechanistic levels in mice still needs to be investigated. Here we show that memory disturbances with altered hippocampal chromatin plasticity in the aging brain of the mouse are associated with gut‐microbiota changes and intragastric administration of allyl sulfide retards age‐related defects. To test the hypothesis, we employed 4‐months age‐matched male wild‐type C57BJ/L6 (WT) mice as control group (Young), 24‐months old age‐matched male WT mice group as aging group (AG) and another 24‐months old age‐matched male WT mice group received daily AS at the dosage of 2mg/kg/b.wt through oral gavage (AG+AS). The results show that Young and AG+AS mice showed higher behavioral proficiency and more robust long‐term and short‐term memory compared to AG mice. Gut microbiota is significantly altered as assessed by the denaturing gradient gel electrophoresis (DGGE) analysis in AG group in compared with Young and AG+AS group. The mechanistic study shows that AG mice display an increased plasma level of circulating non‐coding RNA‐Hotair (lncRNA‐Hotair), as assessed by RT2 lncRNA qPCR Assay. To test whether memory impairment correlates with altered hippocampal chromatin plasticity in a lncRNA‐Hotair dependent manner, we first investigated the hippocampal histone acetylation pattern in the AG group. The data suggest that lncRNA‐Hotair causes a specific deregulation of histone H3 lysine 27 (H3K27) acetylation (ac) at the neuronal derived natriuretic factor (NDNF) promoter of hippocampal tissue of AG group and, therefore, fail to initiate a hippocampal gene transcription associated with memory consolidation. However, administration of AS in the AG group could ameliorate gut dysbiosis and memory functions. In lncRNA‐Hotair‐deficient mice, which are protected from age‐related microbiota changes and memory impairment. Furthermore, restoration of NDNF using recombinant NDNF‐therapy reinstates to the recovery of cognitive abilities. In conclusion, our data suggest that lncRNA‐Hotair upregulation and H3K27ac regulatory activity may represent an early biomarker in the aging mouse brain. In addition, AS could serve as potential anti‐aging therapeutics in treating aging individuals.Support or Funding InformationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.