Dietary zinc status exhibits sex-dependent influence over cerebrovascular function in a mouse model of Alzheimer's disease

Zinc is the second most abundant trace mineral in the body. Within the brain, zinc plays several roles including regulating the blood-brain barrier, immune and inflammation responses, and interacting with amyloid-beta. As we age, zinc becomes a prevalent deficiency, an instance that is exacerbated in patients with Alzheimer’s disease (AD). Currently, zinc is not widely used as a treatment for AD due to the variability in response to treatment seen in humans. To identify if zinc supplementation versus unmitigated zinc deficiency affects cerebrovascular or cognitive function in a model of AD, we placed young (4 mo) APP-KI (APP NLGF) male and female mice on a zinc-standard, high, or low diet for 2 mo. During the intervention, we measured cognitive function by novel object recognition, nest building, and rotarod and arterial stiffness by aortic pulse wave velocity. After 2 mo of diet, we collected posterior cerebral arteries to measure cerebrovascular function through pressure myography. We found that varying zinc in the diet did not impact cognitive function in the mice. Similarly, pulse wave velocity was not affected by diet, however, we did find a significant effect of sex on pulse wave velocity, where females had lower pulse wave velocity, which is aligned with previous studies. Importantly, we identified differences in endothelium-dependent dilation with the zinc diets that were dependent on sex. Males on a high-zinc diet responded significantly more to acetylcholine than males on a low-zinc diet whereas the responses in females were similar between the zinc diets. Females on a low-zinc diet vasodilated more to acetylcholine compared to males on a low-zinc diet. Interestingly, there were also sex differences in the vasodilatory response to insulin. Males on a high-zinc diet dilated more to insulin compared to males on standard and low-zinc diets and compared to females on a high-zinc diet. Varying zinc in diet did not impact endothelium-independent dilation in males, however, we found that females on a low-zinc diet were significantly impaired compared to females on the standard and high-zinc diets. We have identified sex-dependent differences in the response to varying amounts of zinc in the diets in a mouse model of AD. Males on a high-zinc diet showed increased cerebrovascular function compared to males on a low-zinc diet, but this effect was absent in females. These results suggest that the variability of responses to zinc in humans may be due to sex differences. As such, further investigation into the effects of sex and age on the efficacy of zinc interventions is warranted. This project was funded by the Oregon Partnership for Alzheimer’s Research – Oregon Tax Checkoff Alzheimer’s Research Fund 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.