Insulin BBB pharmacokinetics in young apoE male and female transgenic mice

In addition to age, apolipoprotein E4 (E4), female sex, or a combination of both synergistically increase the risk for the development of Alzheimer's disease (AD). Why these risk factors predispose an individual to developing AD later in life is the target of the current investigation. Central nervous system (CNS) insulin resistance is associated with cognitive impairment and AD. CNS insulin is acquired primarily from the circulation and therefore must negotiate the blood-brain barrier (BBB). Thus, changes in BBB transport of insulin could lead to alterations in CNS insulin signaling and resistance, which would then lead to changes in cognition. There has been recent evidence suggesting the relationship between CNS insulin; E4, a risk factor to develop AD as compared to E3; and the female sex in aged individuals and in pre-clinical models. However, this relationship has been largely unexplored at a younger age, in which some of these risk factors could predispose an individual to dysregulation of CNS insulin later in life. Here, we present the first findings of BBB insulin pharmacokinetics in young E3 and E4 male and female targeted replacement (TR) mice. We found that levels of insulin binding the vasculature at the BBB are different due to genotype and sex which could impact the function of the brain endothelial cell. These early alterations could contribute to or fully explain the age-related cognitive changes observed due to CNS insulin signaling in E4 and/or female individuals.