Diurnal Characteristics of the Orexin System Genes and Its Effects on Pathology at Early Stage in 3xTg-AD Mice

Oct 16, 2023Neuromolecular medicine

Daily Patterns of Orexin System Genes and Their Links to Early Disease Signs in a Mouse Model of Alzheimer’s

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Abstract

Significant differences in the diurnal expression profiles of orexin system genes were found in 3xTg-AD mice compared to wild type mice.

The mRNA levels of orexin system genes and key genes related to Alzheimer's disease showed distinct diurnal patterns in the hypothalamus and hippocampus of 3xTg-AD mice.
Positive correlations were observed between the expression of orexin system genes and Alzheimer's disease risk genes or core clock genes in the brains of 3xTg-AD mice.
Expression levels of β-amyloid protein and phosphorylated tau protein were significantly elevated in the hippocampus of 3xTg-AD mice.
Phosphorylated tau protein expression was notably higher at night compared to during the day in 3xTg-AD mice.
These findings suggest that abnormal orexin gene expression may play a crucial role in the development of Alzheimer's disease pathology.

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Orexin and its receptors are closely related to the pathogenesis of Alzheimer's disease (AD). Although the expression of orexin system genes under physiological condition has circadian rhythm, the diurnal characteristics of orexin system genes, and its potential role in the pathogenesis in AD are unknown. In the present study, we hope to elucidate the diurnal characteristics of orexin system genes at the early stage of AD, and to investigate its potential role in the development of AD neuropathology. We firstly detected the mRNA levels of orexin system genes, AD risk genes and core clock genes (CCGs) in hypothalamus and hippocampus in 6-month-old male 3xTg-AD mice and C57BL/6J (wild type, WT) control mice, then analyzed diurnal expression profiles of all genes using JTK_CYCLE algorithm, and did the correlation analysis between expression of orexin system genes and AD risk genes or CCGs. In addition, the expression of β-amyloid protein (Aβ) and phosphorylated tau (p-tau) protein were measured. The results showed that the diurnal mRNA expression profiles of PPO, OX1R, OX2R, Bace2, Bmal1, Per1, Per2 and Cry1 in the hypothalamus, and gene expression of OX1R, OX2R, Bace1, Bmal1, Per1 and Cry2 in the hippocampus in 3xTg-AD mice were different from that in WT mice. Furthermore, there is positive correlation between orexin system genes and AD risk genes or CCGs in the brain in 3xTg-AD mice. In addition, the expression of Aβ and p-tau in hippocampus in 3xTg-AD mice were significantly increased, and the expression of p-tau is higher in night than in day. These results indicate that the abnormal expression profiles of orexin system genes and its interaction with AD risk genes or CCGs might exert important role in the pathogenesis of AD, which will increase the expression of Aβ and p-tau, and accelerate the development of AD.

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Diurnal Characteristics of the Orexin System Genes and Its Effects on Pathology at Early Stage in 3xTg-AD Mice

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