Chronic Stress Contributes to Cognitive Dysfunction and Hippocampal Metabolic Abnormalities in APP/PS1 Mice

• Published in: Cellular physiology and biochemistry Vol. 41; no. 5; pp. 1766 - 1776
• Main Authors: Han, Bing, Wang, Jin-Hua, Geng, Yuan, Shen, Li, Wang, Hua-Long, Wang, Yan-Yong, Wang, Ming-Wei
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.06.2017; Cell Physiol Biochem Press GmbH & Co KG
• Subjects: Aging; Alzheimer's disease; Amino Acids - genetics; Amino Acids - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animal cognition; Animals; Chronic Disease; Cognitive Dysfunction - etiology; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - pathology; Gas chromatography-mass spectrometry; Hippocampus - metabolism; Hippocampus - pathology; Homeostasis; Ketone Bodies - genetics; Ketone Bodies - metabolism; Mass spectrometry; Metabolism; Metabolites; Metabolome; Metabolomics; Mice; Mice, Transgenic; Mutation; Neurosciences; Original Paper; Physiology; Rodents; Scientific imaging; Sphingolipids - genetics; Sphingolipids - metabolism; Stress; Stress response; Stress, Psychological - complications; Stress, Psychological - genetics; Stress, Psychological - metabolism; Stress, Psychological - pathology; Transgenic mice; United States > US; Metabolomics; Gas chromatography-mass spectrometry; Alzheimer’s disease; Stress response; Transgenic mice
• ISSN: 1015-8987; 1421-9778
• DOI: 10.1159/000471869

Background/Aims: Stress response is determined by the brain, and the brain is a sensitive target for stress. Our previous experiments have confirmed that once the stress response is beyond the tolerable limit of the brain, particularly that of the hippocampus, it will have deleterious effects on hippocampal structure and function; however, the metabolic mechanisms for this are not well understood. Methods: Here, we used morris water maze, elisa and gas chromatography-time of flight/mass spectrometry to observe the changes in cognition, neuropathology and metabolomics in the hippocampus of APP/PS1 mice and wild-type (C57) mice caused by chronic unpredictable mild stress (CUMS), we also further explored the correlation between cognition and metabolomics. Results: We found that 4 weeks of CUMS aggravated cognitive impairment and increased amyloid-β deposition in APP/PS1 mice, but did not affect C57 mice. Under non-stress conditions, compared with C57 mice, there were 8 different metabolites in APP/PS1 mice. However, following CUMS, 3 different metabolites were changed compared with untreated C57 mice. Compared to APP/PS1 mice, there were 7 different metabolites in APP/PS1+CUMS mice. Among these alterations, 3-hydroxybutyric acid, valine, serine, beta-alanine and o-phosphorylethanolamine, which are involved in sphingolipid metabolism, synthesis and degradation of ketone bodies, and amino acid metabolism. Conclusion: The results indicate that APP/PS1 mice are more vulnerable to stress than C57 mice, and the metabolic mechanisms of stress-related cognitive impairment in APP/PS1 mice are related to multiple pathways and networks, including sphingolipid metabolism, synthesis and degradation of ketone bodies, and amino acid metabolism.