Santos Ed Wilson, Khatoon Subika, Zheng Yun-Min, Wang Yong-Xiao
Department of Molecular and Cellular Physiology, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208-3479, USA.
Cells. 2025 Aug 15;14(16):1260. doi: 10.3390/cells14161260.
Type 1 diabetes (T1D) is a serious disease which affects millions of people worldwide and is a major factor for vascular contributions to cognitive impairment and dementia (VCID). In this study, we first characterized cognitive and memory impairments, then evaluated their underlying molecular mechanisms, and finally determined sex-dependent effects in male and female mice with streptozotocin (STZ)-induced T1D. Our findings indicated that significant cognitive impairment, memory loss, and vascular dementia occurred in male and female T1D mice. Cerebral artery (CA) blood flow was greatly reduced in the various brain regions tested. ROS generation in isolated cells, mitochondria, and mitochondrial complex III from CA smooth muscle cells (CASMCs) were all increased in T1D. DNA damage and Tau phosphorylation in CASMCs were largely increased. Linear regression analysis revealed that T1D-induced increased blood glucose was highly correlated with increased ROS production and increased VCID. Taken together, we conclude that T1D causes increased mitochondrial complex III ROS production, DNA damage, and Chk2 phosphorylation in CASMC, thereby leading to vascular dementia in both male and female mice; our results further demonstrate that mitochondrial complex III ROS-mediated DNA damage is more significant in male than female mice, which contributes to more serious vascular dementia in the former than the latter.
1型糖尿病（T1D）是一种严重疾病，影响着全球数百万人，并且是血管导致认知障碍和痴呆（VCID）的主要因素。在本研究中，我们首先对认知和记忆障碍进行了特征描述，然后评估了其潜在的分子机制，最后确定了链脲佐菌素（STZ）诱导的T1D雄性和雌性小鼠中的性别依赖性效应。我们的研究结果表明，雄性和雌性T1D小鼠均出现了显著的认知障碍、记忆丧失和血管性痴呆。在测试的各个脑区中，脑动脉（CA）血流量大幅降低。T1D小鼠中，来自CA平滑肌细胞（CASMCs）的分离细胞、线粒体和线粒体复合物III中的活性氧（ROS）生成均增加。CASMCs中的DNA损伤和Tau磷酸化大幅增加。线性回归分析显示，T1D诱导的血糖升高与ROS生成增加和VCID增加高度相关。综上所述，我们得出结论，T1D导致CASMC中线粒体复合物III的ROS生成增加、DNA损伤和Chk2磷酸化，从而导致雄性和雌性小鼠均出现血管性痴呆；我们的结果进一步证明，线粒体复合物III的ROS介导的DNA损伤在雄性小鼠中比雌性小鼠更显著，这导致前者的血管性痴呆比后者更严重。
