Liu Qianshuo, Jiang Meixi, Wang Zhengze, Meng Jihong, Jia Hui, Li Jing, Lin Jiacai, Guo Libin, Gao Lianbo
Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
Cell Biol Toxicol. 2025 Jan 10;41(1):28. doi: 10.1007/s10565-025-09986-6.
Alzheimer's disease (AD), the most prevalent form of dementia in the elderly, involves critical changes such as reduced aerobic glycolysis in astrocytes and increased neuronal apoptosis, both of which are significant in the disease's pathology. In our study, astrocytes treated with amyloid β1-42 (Aβ) to simulate AD conditions exhibited upregulated expressions of small ubiquitin-like modifier (SUMO)-specific protease 1 (SENP1) and Pumilio RNA Binding Family Member 2 (PUM2), alongside decreased levels of Nuclear factor erythroid 2-related factor 2 (NRF2). SENP1 is notably the most upregulated SUMOylation enzyme in Aβ-exposed astrocytes. Functional assays including Ni-Nitrilotriacetic acid (NTA) agarose bead pull-down and co-immunoprecipitation (Co-IP) confirmed SENP1's role in actively deSUMOylating PUM2, thereby enhancing its stability and expression. The interaction between PUM2 and the 3' untranslated region (3'UTR) of NRF2 mRNA reduces NRF2 levels, subsequently diminishing the transcriptional activation of critical glycolytic enzymes, Hexokinase 1 (HK1) and Glucose Transporter 1 (GLUT1). These changes contribute to the observed reduction in glycolytic function in astrocytes, exacerbating neuronal apoptosis. Targeted interventions, such as knockdown of Senp1 or Pum2 or overexpression of NRF2 in APPswe/PSEN1dE9 (APP/PS1) transgenic mice, effectively increased HK1 and GLUT1 levels, decreased apoptosis, and alleviated cognitive impairment. These findings highlight the important roles of the SENP1/PUM2/NRF2 pathway in influencing glucose metabolism in astrocytes, presenting new potential therapeutic targets for AD.
阿尔茨海默病（AD）是老年人中最常见的痴呆形式，涉及关键变化，如星形胶质细胞有氧糖酵解减少和神经元凋亡增加，这两者在该疾病的病理学中都很重要。在我们的研究中，用淀粉样β1-42（Aβ）处理以模拟AD条件的星形胶质细胞表现出小泛素样修饰物（SUMO）特异性蛋白酶1（SENP1）和Pumilio RNA结合家族成员2（PUM2）的表达上调，同时核因子红细胞2相关因子2（NRF2）水平降低。SENP1是暴露于Aβ的星形胶质细胞中上调最明显的SUMO化酶。包括镍-亚氨基三乙酸（NTA）琼脂糖珠下拉和免疫共沉淀（Co-IP）在内的功能测定证实了SENP1在积极去除PUM2的SUMO化方面的作用，从而增强其稳定性和表达。PUM2与NRF2 mRNA的3'非翻译区（3'UTR）之间的相互作用降低了NRF2水平，随后减少了关键糖酵解酶己糖激酶1（HK1）和葡萄糖转运蛋白1（GLUT1）的转录激活。这些变化导致观察到的星形胶质细胞糖酵解功能降低，加剧了神经元凋亡。在APPswe/PSEN1dE9（APP/PS1）转基因小鼠中进行有针对性的干预，如敲低Senp1或Pum2或过表达NRF2，有效地提高了HK1和GLUT1水平，减少了细胞凋亡，并减轻了认知障碍。这些发现突出了SENP1/PUM2/NRF2途径在影响星形胶质细胞葡萄糖代谢中的重要作用，为AD提供了新的潜在治疗靶点。
