Investigating metabolic dysregulation in serum of triple transgenic Alzheimer's disease male mice: implications for pathogenesis and potential biomarkers.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that lacks convenient and accessible peripheral blood diagnostic markers and effective drugs. Metabolic dysfunction is one of AD risk factors, which leaded to alterations of various metabolites in the body. Pathological changes of the brain can be reflected in blood metabolites that are expected to explain the disease mechanisms or be candidate biomarkers. The aim of this study was to investigate the changes of targeted metabolites within peripheral blood of AD mouse model, with the purpose of exploring the disease mechanism and potential biomarkers. Targeted metabolomics was used to quantify 256 metabolites in serum of triple transgenic AD (3 × Tg-AD) male mice. Compared with controls, 49 differential metabolites represented dysregulation in purine, pyrimidine, tryptophan, cysteine and methionine and glycerophospholipid metabolism. Among them, adenosine, serotonin, N-acetyl-5-hydroxytryptamine, and acetylcholine play a key role in regulating neural transmitter network. The alteration of S-adenosine-L-homocysteine, S-adenosine-L-methionine, and trimethylamine-N-oxide in AD mice serum can served as indicator of AD risk. The results revealed the changes of metabolites in serum, suggesting that metabolic dysregulation in periphery in AD mice may be related to the disturbances in neuroinhibition, the serotonergic system, sleep function, the cholinergic system, and the gut microbiota. This study provides novel insights into the dysregulation of several key metabolites and metabolic pathways in AD, presenting potential avenues for future research and the development of peripheral biomarkers.

Targeted metabolomics study of early pathological features in hippocampus of triple transgenic Alzheimer's disease male mice.

Alzheimer's disease (AD) is a serious neurodegenerative disease in people of age 65 or above. The detailed etiology and pathogenesis of AD have not been elucidated yet. In this study, the hippocampi of 2- and 6-month-old triple transgenic Alzheimer's disease male mice and age-sex-matched wild-type (WT) mice were analyzed by using targeted metabolomics approach. Compared with WT mice, 24 and 60 metabolites were found with significant differences in 2- and 6-month-old AD mice. Among these, 14 metabolites were found common while 10 metabolites showed consistent variable trends in both groups. These differential metabolites are found associated with amino acid, lipid, vitamin, nucleotide-related base, neurotransmitter and energy metabolisms, and oxidative stress. The results suggest that these differential metabolites might play a critical role in AD pathophysiology, and may serve as potential biomarkers for AD. Moreover, the results highlight the involvement of abnormal purine, pyrimidine, arginine, and proline metabolism, along with glycerophospholipid metabolism in early pathology of AD. For the first time, several differential metabolites are found to be associated with AD in this study. Targeted metabolomics can be used for rapid and accurate quantitative analysis of specific target metabolites associated with AD.

Targeted Metabolomic Analysis of the Eye Tissue of Triple Transgenic Alzheimer's Disease Mice at an Early Pathological Stage.

Alzheimer's disease (AD) is a severe neurodegenerative disease in older people. Despite some consensus on pathogenesis of AD established by previous researches, further elucidation is still required for better understanding. This study analyzed the eye tissues of 2- and 6-month-old triple transgenic AD (3 × Tg-AD) male mice and age-sex-matched wild-type (WT) mice using a targeted metabolomics approach. Compared with WT mice, 20 and 44 differential metabolites were identified in 2- and 6-month-old AD mice, respectively. They were associated with purine metabolism, pantothenate and CoA biosynthesis, pyruvate metabolism, lysine degradation, glycolysis/gluconeogenesis, and pyrimidine metabolism pathways. Among them, 8 metabolites presented differences in both the two groups, and 5 of them showed constant trend of change. The results indicated that the eye tissues of 3 × Tg-AD mice underwent changes in the early stages of the disease, with changes in metabolites observed at 2 months of age and more pronounced at 6 months of age, which is consistent with our previous studies on hippocampal targeted metabolomics in 3 × Tg-AD mice. Therefore, a joint analysis of data from this study and previous hippocampal study was performed, and the differential metabolites and their associated mechanisms were similar in eye and hippocampal tissues, but with tissue specificity.