Wang Xin-Ru, Huang Shan-Shan, Wang Meng, Lin Jin-Hong, Wang Jian-Tao, Ren Jiao-Qi, He Cheng-Feng, Xue Wen-Jiao, Wang Yin, Wang Xue-Chun, Zhang Yan-Li, Xiao Ji-Chang, Guo Jing-Chun, Zhou Hou-Guang
Department of Geriatric Neurology of Huashan Hospital, National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China.
Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China.
Front Mol Neurosci. 2025 Aug 8;18:1617543. doi: 10.3389/fnmol.2025.1617543. eCollection 2025.
S-palmitic acid-9-hydroxy stearic acid (SP), a newly characterized endogenous lipid with multifaceted biological activities, is poised to shed light on its potential in diabetes-related cognitive disorder (DRCD). This study aims to uncover the effects of SP on DRCD and the underlying mechanisms.
C57BL/6 mice were fed with high-fat diet for 5 months to induce type 2 diabetes mellitus (T2DM). Subsequently, they received bilateral hippocampal injections of adeno-associated virus (AAV) carrying carbonic anhydrase III (CAIII) shRNA or control shRNA. Following one-month treatment with SP or vehicle, cognitive function was assessed using the Morris water maze and Y-maze tests. Oxidative stress and apoptosis were measured by Enzyme-linked Immunosorbent Assay (ELISA), and hippocampal neuronal morphology was examined through HE, Nissl, or NeuN staining. RNA sequencing (RNA seq), cell viability, tetramethylrhodamine ethyl ester (TMRE) staining, and mitoSOX assays were also performed in cultured PC12 cells.
Our findings demonstrated that CAIII played a pivotal role in enhancing cognitive function in T2DM mice by improving spatial memory. SP ameliorated hippocampal injury by CAIII-mediated AMPK/Sirt1/PGC1α pathway, Bcl-2/Bax ratio elevation, and cleaved-Caspase 3 reduction. CAIII participated in various biological processes in the effects of SP on PC12 cells, including cell viability, lactate dehydrogenase (LDH) release, antioxidant enzymes, the maintenance of mitochondrial membrane potential, and the reduction of mitochondrial reactive oxygen species (ROS).
Our study revealed that CAIII was integral to the effects of SP on DRCD, suggesting its potential as a therapeutic target for DRCD.
S-棕榈酸-9-羟基硬脂酸（SP）是一种新发现的具有多种生物活性的内源性脂质，有望揭示其在糖尿病相关认知障碍（DRCD）中的潜力。本研究旨在揭示SP对DRCD的影响及其潜在机制。
将C57BL/6小鼠高脂喂养5个月以诱导2型糖尿病（T2DM）。随后，对其双侧海马注射携带碳酸酐酶III（CAIII）短发夹RNA（shRNA）或对照shRNA的腺相关病毒（AAV）。用SP或溶剂处理1个月后，使用莫里斯水迷宫和Y迷宫试验评估认知功能。通过酶联免疫吸附测定（ELISA）测量氧化应激和细胞凋亡，并通过苏木精-伊红（HE）、尼氏或神经元核抗原（NeuN）染色检查海马神经元形态。还在培养的PC12细胞中进行了RNA测序（RNA seq）、细胞活力、四甲基罗丹明乙酯（TMRE）染色和线粒体超氧化物检测。
我们的研究结果表明，CAIII通过改善空间记忆在增强T2DM小鼠认知功能中起关键作用。SP通过CAIII介导的AMPK/沉默信息调节因子1（Sirt1）/过氧化物酶体增殖物激活受体γ共激活因子1α（PGC1α）途径、提高Bcl-2/Bax比值和降低裂解的半胱天冬酶3来改善海马损伤。CAIII参与了SP对PC12细胞影响的各种生物学过程，包括细胞活力、乳酸脱氢酶（LDH）释放、抗氧化酶、线粒体膜电位的维持以及线粒体活性氧（ROS）的减少。
我们的研究表明，CAIII是SP对DRCD影响所必需的，提示其作为DRCD治疗靶点的潜力。
