Objective:Using a humanized APOE3/4 (Alzheimer’s disease genetic risk allele) mouse model we investigated the potential modulating effects of exercise on systemic risk factors and the ability of this mouse model to translate to active or sedentary, midlife, human participants. We present preliminary results of an ongoing, translational pilot study.Participants and Methods:26 Midlife individuals, ages 40-65, were recruited from the community and dichotomized into active or sedentary groups following health screening and cognitive assessment. Blood samples were drawn from human participants for lipid assessment and other general health measures as well as peripheral growth factors concentrations (VEGF, BDNF and FGF21). Traditional, transgenic mouse models have helped the scientific community to understand biological mechanisms of Alzheimer’s disease (AD), but they do not develop significant neuronal loss, a hallmark of AD pathology. The MODEL-AD consortium has created a new “humanized” APOE4 model that has the human APOE4 allelic sequence in place of the mouse APOE gene; the model has shown known human phenotypes including deficits in cholesterol trafficking, amyloid clearance and BBB integrity. Of upmost importance, this model does not develop a full AD phenotype indicating that additional genetics and/or environmental factors are required as would be seen in human populations. We used males and females of this model to complete identical sedentary and active measures of each APOE genotype.Results:Lipid and general health marker assessment between mouse and human were similar and reproduced published literature. In both humans and mice we saw increased total cholesterol and HDL in active females and decreased total cholesterol and HDL in active males. We also saw similar relationships between APOE genotype, sex, and activity with regards to triglycerides. Although total cholesterol, HDL and LDL measures are the primary lipids needed to confirm or deny translation, other lipid measurements were not equivalent between the two models. Growth factor assessment in both species are also similar and reproduce published literature with regards to VEGF and BDNF as we see trending elevated levels in the active group. Less published on is the finding seen between active females and these elevated growth factors levels; our results indicates that although elevated as a result of exercise, this increase may be more prominent in females.Conclusions:Based on the results found here we conclude that The Jackson Laboratory’s humanized APOE3/4 mouse model is a translatable model of vascular dysfunction, dementia and Alzheimer’s disease. We also conclude that exercise modulates these aspects by growth factor activation and increases resulting in downstream effects that reduce peripheral vascular risk factors and therefore reduce the risk of Alzheimer’s disease as a result of neuroinflammation. Complete, APOE genotype results from human participants are still ongoing. Descriptive analysis is limited by human samples size.

中文翻译：

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6 运动诱导的生长因子增加直接和间接降低系统性血管风险参数：临床前阿尔茨海默病和血管性痴呆的中年人类和动物模型的转化项目

目的：使用人源化 APOE3/4（阿尔茨海默病遗传风险等位基因）小鼠模型，我们研究了运动对系统性危险因素的潜在调节作用，以及该小鼠模型转化为活跃或久坐的中年人类参与者的能力。我们介绍了一项正在进行的转化性试点研究的初步结果。 参与者和方法：从社区招募 26 名 40-65 岁的中年个体，并在健康筛查和认知评估后分为活跃组和久坐组。从人类参与者身上抽取血液样本，用于血脂评估和其他一般健康指标以及外周生长因子浓度（VEGF、BDNF 和 FGF21）。传统的转基因小鼠模型帮助科学界了解阿尔茨海默病 (AD) 的生物学机制，但它们并没有出现明显的神经元损失，而这是 AD 病理学的一个标志。MODEL-AD联盟创建了一种新的“人源化”APOE4模型，用人类APOE4等位基因序列代替小鼠APOE基因；该模型显示了已知的人类表型，包括胆固醇运输、淀粉样蛋白清除和血脑屏障完整性方面的缺陷。最重要的是，该模型没有形成完整的 AD 表型，表明需要额外的遗传和/或环境因素，就像在人群中看到的那样。我们使用该模型的雄性和雌性对每种 APOE 基因型完成相同的久坐和活动测量。结果：小鼠和人类之间的脂质和一般健康标志物评估相似，并复制了已发表的文献。在人类和小鼠中，我们发现活跃的雌性中的总胆固醇和高密度脂蛋白增加，而活跃的雄性中的总胆固醇和高密度脂蛋白降低。我们还发现 APOE 基因型、性别和甘油三酯活性之间存在类似关系。尽管总胆固醇、HDL 和 LDL 测量是确认或否认翻译所需的主要脂质，但两个模型之间的其他脂质测量并不相同。两个物种的生长因子评估也相似，并且复制了有关 VEGF 和 BDNF 的已发表文献，因为我们看到活性组中水平呈升高趋势。较少发表的是活跃女性与这些升高的生长因子水平之间的发现；我们的结果表明，虽然由于运动而升高，但这种升高在女性中可能更为明显。结论：根据此处发现的结果，我们得出结论，杰克逊实验室的人源化 APOE3/4 小鼠模型是血管功能障碍、痴呆的可转化模型和阿尔茨海默病。我们还得出结论，运动通过生长因子激活来调节这些方面，并增加下游效应，从而减少外周血管危险因素，从而降低因神经炎症而患阿尔茨海默病的风险。来自人类参与者的完整 APOE 基因型结果仍在进行中。