Related Experiment Video
Updated: Dec 17, 2025
Enrichment of Mammalian Tissues and Xenopus Oocytes with Cholesterol
Published on: March 25, 2020
27-Hydroxycholesterol contributes to cognitive deficits in APP/PS1 transgenic mice through microbiota dysbiosis and
Ying Wang1, Yu An1, Weiwei Ma1
1School of Public Health, Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing, 100069, China.
Background:
Research on the brain-gut-microbiota axis has led to accumulating interest in gut microbiota dysbiosis and intestinal barrier dysfunction in Alzheimer's disease (AD). Our previous studies have demonstrated neurotoxic effects of 27-hydroxycholesterol (27-OHC) in in vitro and in vivo models. Here, alterations in the gut microbiota and intestinal barrier functions were investigated as the possible causes of cognitive deficits induced by 27-OHC treatment.
Methods:
Male APP/PS1 transgenic and C57BL/6J mice were treated for 3 weeks with 27-OHC (5.5 mg/kg/day, subcutaneous injection) and either a 27-OHC synthetase inhibitor (anastrozole, ANS) or saline. The Morris water maze and passive avoidance test were used to assess cognitive impairment. Injuries of the intestine were evaluated by histopathological examination. Intestinal barrier function was assessed by plasma diamine oxidase (DAO) activity and D-lactate. Systemic and intestinal inflammation were evaluated by IL-1β, TNF-α, IL-10, and IL-17 concentrations as determined by ELISA. The fecal microbiome and short-chain fatty acids (SCFAs) were analyzed using 16S rDNA sequencing and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Tight junction proteins were evaluated in the ileum and colon by qRT-PCR and Western blots. Tight junction ultrastructure was examined by transmission electron microscopy.
Results:
Treatment with 27-OHC resulted in severe pathologies in the ileum and colon. There was impaired intestinal barrier integrity as indicated by dilated tight junctions and downregulation of tight junction proteins, including occludin, claudin 1, claudin 5, and ZO-1, and signs of inflammation (increased IL-1β, TNF-α, and IL-17). Fecal 16S rDNA sequencing and taxonomic analysis further revealed a decreased abundance of Roseburia and reduced fecal levels of several SCFAs in 27-OHC-treated mice. Meanwhile, co-treatment with ANS reduced intestinal inflammation and partially preserved intestinal barrier integrity in the presence of 27-OHC.
Conclusions:
The current study demonstrates for the first time that 27-OHC treatment aggravates AD-associated pathophysiological alterations, specifically gut microbiota dysbiosis and intestinal barrier dysfunction, which suggests that the gut microbiome and intestinal barrier function warrant further investigation as potential targets to mitigate the neurotoxic impact of 27-OHC on cognitive function and the development of AD.
Insights
27-hydroxycholesterol (27-OHC) worsens Alzheimer's disease (AD) by disrupting the gut microbiome and intestinal barrier. Targeting these gut issues may mitigate 27-OHC's neurotoxic effects on cognition.
Area of Science:
- Neuroscience
- Microbiology
- Gastroenterology
Background:
- Growing interest in the brain-gut-microbiota axis in Alzheimer's disease (AD).
- Previous research demonstrated neurotoxic effects of 27-hydroxycholesterol (27-OHC).
- Investigating gut microbiota and intestinal barrier as potential causes of 27-OHC-induced cognitive deficits.
Purpose of the Study:
- To investigate the impact of 27-OHC on gut microbiota and intestinal barrier function.
- To explore the role of these alterations in cognitive deficits associated with 27-OHC.
- To assess the potential of targeting gut health to mitigate 27-OHC neurotoxicity.
Main Methods:
- Male APP/PS1 transgenic and C57BL/6J mice were treated with 27-OHC and an anastrozole (ANS) inhibitor or saline.
- Cognitive function was assessed using Morris water maze and passive avoidance tests.
- Intestinal barrier integrity, inflammation, gut microbiome composition, and tight junction proteins were analyzed.
Main Results:
- 27-OHC treatment caused significant intestinal pathologies, impaired barrier integrity, and inflammation.
- Reduced abundance of Roseburia and short-chain fatty acids (SCFAs) were observed in the gut microbiota.
- Anastrozole co-treatment partially preserved intestinal barrier integrity and reduced inflammation.
Conclusions:
- 27-OHC treatment exacerbates AD-associated gut microbiota dysbiosis and intestinal barrier dysfunction.
- These gut alterations contribute to cognitive deficits and AD pathogenesis.
- The gut microbiome and intestinal barrier represent potential therapeutic targets for mitigating 27-OHC's neurotoxic effects in AD.
