Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, China.
Key Laboratory of Cellular Physiology, Ministry of Education, Taiyuan, Shanxi, China.
Neuromolecular Med. 2023 Dec;25(4):632-643. doi: 10.1007/s12017-023-08767-w. Epub 2023 Oct 16.
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.
食欲素及其受体与阿尔茨海默病（AD）的发病机制密切相关。虽然在生理条件下，食欲素系统基因的表达具有昼夜节律，但食欲素系统基因的昼夜特征及其在 AD 发病机制中的潜在作用尚不清楚。本研究旨在阐明 AD 早期食欲素系统基因的昼夜特征，并探讨其在 AD 神经病理学发展中的潜在作用。我们首先检测了 6 月龄雄性 3xTg-AD 小鼠和 C57BL/6J（野生型，WT）对照组小鼠下丘脑和海马中食欲素系统基因、AD 风险基因和核心时钟基因（CCGs）的 mRNA 水平，然后使用 JTK_CYCLE 算法分析所有基因的昼夜表达谱，并对食欲素系统基因与 AD 风险基因或 CCGs 的表达进行相关性分析。此外，还测量了β-淀粉样蛋白（Aβ）和磷酸化 tau 蛋白（p-tau）的表达。结果表明，3xTg-AD 小鼠下丘脑 PPO、OX1R、OX2R、Bace2、Bmal1、Per1、Per2 和 Cry1 以及海马 OX1R、OX2R、Bace1、Bmal1、Per1 和 Cry2 的昼夜 mRNA 表达谱与 WT 小鼠不同。此外，3xTg-AD 小鼠脑内食欲素系统基因与 AD 风险基因或 CCGs 之间存在正相关。此外，3xTg-AD 小鼠海马 Aβ和 p-tau 的表达明显增加，且 p-tau 在夜间的表达高于白天。这些结果表明，食欲素系统基因的异常表达谱及其与 AD 风险基因或 CCGs 的相互作用可能在 AD 的发病机制中发挥重要作用，从而增加 Aβ和 p-tau 的表达，加速 AD 的发展。
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