Molecular pathogenesis of sex-specificcerebral vascular contributions to cognitive impairment and dementia in type-1 diabetes

Type 1 diabetes (T1D) is not only a common serious disease affecting millions of people worldwide, but also a major factor for vascular contributions to cognitive impairment and dementia (VCID). In this study, we first characterized rarely-reported cognitive and memory impairments, then evaluated the 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 VCID occurred in male and female T1D mice. Cerebral artery (CA) blood flow was deeply reduced in various brain regions tested. Reactive oxygen species (ROS) generation in isolated cells, mitochondria and mitochondrial complex III from CA smooth muscle (CASM) tissues were all increased in diabetic mice. DNA damage (demonstrated by check kinase 2, Chk2 phosphorylation) and Tau phosphorylation in CASMs were largely increased. Linear regression analysis revealed that T1D-induced increased blood glucose was highly correlated with increased ROS production and increased VCID, and increased ROS production was also highly correlated with increased CVID. T1D-evoked complex III ROS production and DNA damage were greater in male than female mice. Taken together, we conclude that T1D causes increased mitochondrial complex III ROS production, DNA damage, and Chk2 phosphorylation in CASM, thereby leading to VCID 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, which contributes to more serious VCID in former than the later T1D. Supported by NIH R01HL164941 and NIH R03AG070784 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.