Graduate School of Environmental Science Program, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan.
Open Innovation Laboratory for Food and Medicinal Resource Engineering, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Tennodai, Tsukuba 305-8572, Japan.
Int J Mol Sci. 2023 Sep 8;24(18):13867. doi: 10.3390/ijms241813867.
With the progression of an aging society, cognitive aging has emerged as a pressing concern necessitating attention. The senescence-accelerated mouse-prone 8 (SAMP8) model has proven instrumental in investigating the early stages of cognitive aging. Through an extensive examination of molecular changes in the brain cortex, utilizing integrated whole-genome transcriptomics, our principal aim was to uncover potential molecular targets with therapeutic applications and relevance to drug screening. Our investigation encompassed four distinct conditions, comparing the same strain at different time points (1 year vs. 16 weeks) and the same time point across different strains (SAMP8 vs. SAMR1), namely: physiological aging, accelerated aging, early events in accelerated aging, and late events in accelerated aging. Focusing on key functional alterations associated with aging in the brain, including neurogenesis, synapse dynamics, neurometabolism, and neuroinflammation, we identified candidate genes linked to these processes. Furthermore, employing protein-protein interaction (PPI) analysis, we identified pivotal hub genes involved in interactions within these functional domains. Additionally, gene-set perturbation analysis allowed us to uncover potential upstream genes or transcription factors that exhibited activation or inhibition across the four conditions. In summary, our comprehensive analysis of the SAMP8 mouse brain through whole-genome transcriptomics not only deepens our understanding of age-related changes but also lays the groundwork for a predictive model to facilitate drug screening for cognitive aging.
随着老龄化社会的发展，认知衰老已成为一个紧迫的问题，需要引起关注。加速老化敏感 8 号（SAMP8）小鼠模型已被证明在研究认知衰老的早期阶段非常有用。通过对大脑皮层的分子变化进行广泛的检查，利用整合的全基因组转录组学，我们的主要目标是发现具有治疗应用和药物筛选相关性的潜在分子靶标。我们的研究包括四个不同的条件，比较了同一品系在不同时间点（1 年与 16 周）和同一时间点在不同品系（SAMP8 与 SAMR1）的分子变化：生理衰老、加速衰老、加速衰老的早期事件和加速衰老的晚期事件。我们关注与大脑衰老相关的关键功能变化，包括神经发生、突触动态、神经代谢和神经炎症，确定了与这些过程相关的候选基因。此外，通过蛋白质-蛋白质相互作用（PPI）分析，我们确定了这些功能域内相互作用的关键枢纽基因。此外，基因集扰动分析使我们能够发现四个条件下表现出激活或抑制的潜在上游基因或转录因子。总之，我们通过全基因组转录组学对 SAMP8 小鼠大脑进行的全面分析不仅加深了我们对与年龄相关的变化的理解，还为预测模型奠定了基础，以促进认知衰老的药物筛选。
