Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America.
PLoS One. 2020 Jan 31;15(1):e0228455. doi: 10.1371/journal.pone.0228455. eCollection 2020.
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.
除了年龄、载脂蛋白 E4（E4）、女性性别或两者的组合之外，协同作用还会增加患阿尔茨海默病（AD）的风险。这些风险因素为什么会使个体在以后的生活中更容易患上 AD 是目前研究的目标。中枢神经系统（CNS）胰岛素抵抗与认知障碍和 AD 有关。CNS 胰岛素主要来自循环，因此必须通过血脑屏障（BBB）。因此，BBB 对胰岛素的转运变化可能导致 CNS 胰岛素信号和抵抗的改变，从而导致认知的改变。最近有证据表明，中枢神经系统胰岛素；E4，与 E3 相比，是导致 AD 的危险因素；以及老年个体和临床前模型中的女性性别之间的关系。然而，这种关系在年轻时很大程度上尚未得到探索，在年轻时，这些风险因素中的一些可能会使个体在以后的生活中容易出现中枢神经系统胰岛素失调。在这里，我们介绍了年轻的 E3 和 E4 雄性和雌性靶向替换（TR）小鼠 BBB 胰岛素药代动力学的第一个发现。我们发现，由于基因型和性别，BBB 血管中与胰岛素结合的水平不同，这可能会影响脑内皮细胞的功能。这些早期的改变可能会导致或完全解释由于 CNS 胰岛素信号在 E4 和/或女性个体中观察到的与年龄相关的认知变化。
