472-P: Molecular Pathogenesis of Sex-Specific Vascular Contributions to Cognitive Impairment and Dementia and in Type 1 Diabetes

Introduction & Objective: Type 1 diabetes (T1D) is a serious disease that affects millions of people worldwide and is a major factor for vascular contributions to cognitive impairment and dementia (VCID). However, whether and how sex affects VCID in diabetics is rarely reported. In this study, we compared cognitive and memory impairments in male and female mice with T1D and evaluated the underlying molecular mechanisms.

Methods: We injected streptozotocin (STZ) and then measured cerebral blood flow, ROS production, Tau, and Chk2 expression by Western blotting.

Results: Our findings indicate that intraperitoneal STZ-injection induced T1D in both genders of mice, showing largely elevated blood glucose, and decreased body weight. However, male diabetic mice showed greater cognitive impairment determined by an open-field test and memory loss measured by a novel object recognition test. Interestingly, ROS generation in isolated mitochondria and mitochondrial complex III from cerebral arterial smooth muscle (CASM) tissues was greater in male diabetic mice. ROS production in isolated mitochondria and mitochondrial complex III from cerebral cortex tissues was increased similarly in both male and female diabetic mice. We further found that male diabetic mice had higher DNA damage, as demonstrated by greater check kinase 2 (Chk2) phosphorylation in CASM tissues. Tau phosphorylation in CASM tissues was also largely increased in diabetic mice; this diabetic increase was no different between males and females. Noticeably, mitochondrial and complex III ROS production, Chk2, and tau phosphorylation all had similar increases in cerebral cortex tissues from both male and female diabetic mice.

Conclusion: Taken together, we conclude that T1D may cause greater mitochondrial complex III ROS production, greater DNA damage and greater Chk2 phosphorylation in male CASM tissues, thereby leading to more serious cognitive impairment and memory loss in male than female T1D.