Chen Xia, Lin Cong, He Chengfen, Li Kaikai, Gao Jianmei, Gong Qihai, Li Fei
Key Laboratory of Basic Pharmacology of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi, China.
Department of Psychiatry, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
J Alzheimers Dis. 2025 Jan;103(2):616-626. doi: 10.1177/13872877241303949. Epub 2025 Jan 15.
One of the hallmark pathological characteristics of Alzheimer's disease (AD) is amyloid-β (Aβ) accumulated in brain, which is mainly derived from the proteolytic processing of amyloid-β protein precursor (AβPP). The ubiquitin-proteasome system is able to reduce Aβ generation by ubiquitination and degradation of AβPP. Icariin (ICA), a flavonoid isolated from Maxim., has been reported that it could regulate the metabolism of AβPP and reduce the Aβ level in AD and models.
To investigate whether the effect of ICA on AβPP and Aβ is related to AβPP ubiquitination.
We used and models to observe the effect of ICA on AβPP ubiquitination as well as to investigate the effect of HMG-CoA reductase degradation protein 1 (HRD1), an E3 ubiquitin-protein ligase, on the processing of AβPP ubiquitination.
This study showed that ICA improved the cognitive abilities of APP/PS1 AD mice in Morris Water Maze and Y-maze tests, upregulated HRD1 expression, subsequently elevated the total ubiquitination and K48-linked polyubiquitination of AβPP level, as well as increased AβPP degradation. Moreover, silenced gene abolished the aforementioned effects of ICA. Furthermore, ICA decreased the location of AβPP in the early endosome, where AβPP is cleaved into Aβ, evidenced by reducing the co-localization of AβPP and early endosome antigen 1 (EEA1).
This study demonstrated that ICA increased AβPP degradation by upregulating HRD1 mediated ubiquitination.
阿尔茨海默病（AD）的标志性病理特征之一是大脑中淀粉样β蛋白（Aβ）的积累，其主要来源于淀粉样β蛋白前体（AβPP）的蛋白水解加工。泛素-蛋白酶体系统能够通过对AβPP进行泛素化和降解来减少Aβ的生成。淫羊藿苷（ICA）是从淫羊藿中分离出的一种黄酮类化合物，据报道它可以调节AβPP的代谢并降低AD模型中的Aβ水平。
研究ICA对AβPP和Aβ的影响是否与AβPP泛素化有关。
我们使用APP/PS1和SH-SY5Y模型观察ICA对AβPP泛素化的影响，并研究E3泛素蛋白连接酶HMG-CoA还原酶降解蛋白1（HRD1）对AβPP泛素化加工的影响。
本研究表明，ICA在莫里斯水迷宫和Y迷宫试验中提高了APP/PS1 AD小鼠的认知能力，上调了HRD1表达，随后提高了AβPP水平的总泛素化和K48连接的多聚泛素化，以及增加了AβPP降解。此外，沉默HRD1基因消除了ICA的上述作用。此外，ICA减少了AβPP在早期内体中的定位，AβPP在早期内体中被切割成Aβ，这通过减少AβPP与早期内体抗原1（EEA1）的共定位得到证明。
本研究表明，ICA通过上调HRD1介导的泛素化增加了AβPP降解。
