Abstract
Metabolic dysfunction increases with age and is a contributing factor to Alzheimer's disease (AD) development. We have previously observed impaired insulin sensitivity and glucose homeostasis in the APP/PS1 model of AD. To improve these parameters, we chronically exposed male and female mice to mild hypothermic environmental temperature (eT), which positively modulates metabolism. Although a hypothermic eT normalized insulin sensitivity, glucose tolerance was still impaired in both sexes of AD mice. We observed increased plasma glucagon and B-cell activating factor in both sexes, but additional sexually dimorphic mechanisms may explain the impaired glucose homeostasis in AD mice. Hepatic Glut2 was decreased in females while visceral adipose tissue TNFα was increased in male APP/PS1 mice. A mild hypothermic eT did not improve spatial learning and memory in either sex and increased amyloid plaque burden in male APP/PS1 mice. Overall, plasma markers of glucose homeostasis and AD pathology were worse in females compared to male APP/PS1 mice suggesting a faster disease progression. This could affect the therapeutic outcomes if interventional strategies are administered at the same chronological age to male and female APP/PS1 mice. Furthermore, this data suggests a dichotomy exists between mechanisms to improve metabolic function and cognitive health that may be further impaired in AD.