An Investigation into the Role of Iron, Copper, and Gender in a Transgenic Mouse Model of Alzheimer's Disease.

Abstract

Age-related diseases are more prevalent due to increasing longevity, with this comes increasing dietary supplementation to maintain a healthy lifestyle. Alzheimer's disease (AD) is the primary cause of dementia and the sixth leading cause of death in the United States. Previous studies of transgenic AD mouse models have found that long-term dietary supplementation of zinc (Zn) impairs spatial memory, while copper (Cu) shows remediation of this impairment. Iron (Fe) shows a similar impairment in these tasks, but the potential effects of remediation by Cu have not been studied. In humans, being female is a risk factor for cognitive impairment in AD, therefore it is important to examine gender differences in AD. To examine the effect and interaction of Fe and Cu on cognitive function, male and female transgenic (Tg)CRND8 and wild-type (Wt) mice were administered enhanced drinking water for 5 months: Fe (10ppm FeNO3), Fe+Cu (10ppm FeNO3 + 0.2ppm CuNO3), Cu (0.2ppm CuNO3), and LW. Assessments included the novel object recognition task (NOR; discrimination task) and the Morris water maze (MWM; spatial memory). Histological analysis was conducted on the brain to examine the plaque load, metal content, ceruloplasmin levels, and amyloid levels in these mice. In NOR, Tg Fe+Cu-treated animals showed decreased object recognition compared to Tg LW animals, while Wt Fe+Cu-treated animals performed well. In MWM, only the Fe+Cu-treated animals did not have a decrease in latency and were significantly different from the LW, who were the fastest. Even in normal animals, high levels of Fe+Cu showed negative effects. CRND8 animals were impaired on all assessed measures of learning and memory (NOR and MWM) compared to Wt animals. Females and males perform differently in behavioral tasks dependent upon the type of task. The level of NOR differed between male and female Wt mice, but not Tg. This indicates that female Wt mice are better at this task than male Wt mice; however, once these animals develop signs of AD the difference between the sexes disappears. In contrast, in MWM, males swam faster to the platform than females, and spent less time around the edge of the pool. This was the most pronounced in Tg males compared to Tg females. Sex differences were seen across the varying behavioral tasks of learning and memory, emphasizing the importance of studying both sexes. Plaque load analysis indicated that Fe+Cu-treated and LW Tg animals had the highest plaque burden, while Cu-treated animals had the lowest plaque burden. Females had more plaque area than males, with female Fe+Cu animals showing the highest plaque load of all animals. This measurement of plaque burden may be not be a predictive measure of NOR, but it may be predictive of MWM and it may be due to location of plaque accumulation. The reason may be due to the brain regions required for the completion of the task; MWM depends on the hippocampus, while the hippocampus and entorhinal cortex are required for NOR. Fe+Cu animals had more severe impairments on discrimination and spatial tasks than LW, Fe, or Cu groups alone, which is in contrast to previous findings where Cu remediates impairments caused by Zn. This study showed that it is the balance of metals, not just an overload of a specific metal, which cause harm or not.