Yang Xuehan, Geng Xinru, Xu Zhuoyan, Xu Yang, Han Hao, Zhang Qiang, Jin Honglian, Wang Yuxin, Sun Bin, Zhang Ming, Zhang Siwei, Chen Li
College of Basic Medical Sciences, Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China.
School of Nursing, Jilin University, Changchun, 130021, China.
Alzheimers Res Ther. 2025 Sep 15;17(1):203. doi: 10.1186/s13195-025-01861-0.
Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is characterized by cognitive decline and memory impairment. Brain aging is indisputably the most significant risk factor for AD. Given that aging is a fundamental driving force behind the onset of AD, identifying the aging - regulated genes that contribute to AD development is of utmost importance. Such genes might hold the key to preventing AD or delaying the transition from normal aging to the disease state. In the present study, a comprehensive bioinformatic analysis was conducted on brain transcriptomic datasets obtained from both aging individuals and those with Alzheimer's disease. Among the shared differentially expressed genes, eight genes were found to be downregulated in both aging and AD datasets. Notably, reduced expression of adaptor protein complex 1 sigma 1 subunit (Ap1s1) was validated across multiple mouse models with varying degree of dementia, including aged mice, senescence-accelerated SAMP8 mice, 5xFAD amyloidosis mice, as well as cellular models, including senescent Neuro-2a (N2a) cells, and Aβ-treated or expressing N2a neurons. Functional studies revealed that Ap1s1 knockdown induced cellular senescence without directly impairing viability. However, Ap1s1 silencing exacerbated neuronal vulnerability to oxidative stress (H₂O₂) and Aβ toxicity, manifesting as Golgi-dispersion and reduced survival. Proteomic profiling following Ap1s1 depletion implicated dysregulation of rRNA modifications in the nucleus and cytosol, Golgi-associated vesicle biogenesis. These findings position Ap1s1 as a critical aging-related gene at the nexus of brain aging and AD pathogenesis, whose decline may predispose neurons to Alzheimer's-related insults. As such, Ap1s1 may represent a potential therapeutic target for mitigating aging-related cognitive decline and delaying the onset of AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征为认知能力下降和记忆障碍。脑老化无疑是AD最重要的风险因素。鉴于老化是AD发病的根本驱动力，识别促成AD发展的老化调节基因至关重要。此类基因可能是预防AD或延缓从正常老化向疾病状态转变的关键。在本研究中，对从老化个体和阿尔茨海默病患者获取的脑转录组数据集进行了全面的生物信息学分析。在共同的差异表达基因中，发现有八个基因在老化和AD数据集中均下调。值得注意的是，衔接蛋白复合体1西格玛1亚基（Ap1s1）的表达降低在多种不同程度痴呆的小鼠模型中得到验证，包括老年小鼠、衰老加速的SAMP8小鼠、5xFAD淀粉样变性小鼠，以及细胞模型，包括衰老的神经2a（N2a）细胞，以及经Aβ处理或表达Aβ的N2a神经元。功能研究表明，Ap1s1基因敲低诱导细胞衰老但不直接损害细胞活力。然而，Ap1s1基因沉默加剧了神经元对氧化应激（H₂O₂）和Aβ毒性的易感性，表现为高尔基体分散和存活率降低。Ap1s1缺失后的蛋白质组分析表明，细胞核和细胞质中的rRNA修饰、与高尔基体相关的囊泡生物发生存在失调。这些发现将Ap1s1定位为脑老化与AD发病机制之间关键的衰老相关基因，其表达下降可能使神经元易受阿尔茨海默病相关损伤。因此，Ap1s1可能代表一个潜在的治疗靶点，用于减轻与衰老相关的认知能力下降并延缓AD的发病。
