Brain networks in mouse models of aging

患有阿尔茨海默病的人数迅速增长，只有25%的人得到了诊断； 我们仍然不知道它的病因，也不知道有有效的治疗方法。检查导致转换的因素 从正常到病理性衰老，我们主要关注载脂蛋白E等位基因的多态。风险增加的原因，或 相反，主要的载脂蛋白E等位基因所赋予的韧性是未知的。APOE4/4型是主要的致病基因 晚发性阿尔茨海默病(AD)的遗传风险，并与发展为轻度阿尔茨海默病的30%-55%的风险有关 85岁时认知障碍或阿尔茨海默病，而APOE3/3基因携带者的这一比例为10-15%。相比之下，APOE2是 在AD患者中表达不足，它与长寿有关。为了帮助理解 载脂蛋白E基因及其产物差异化调节大脑及其回路的机制 从健康老龄化转向病理性老龄化，我们将采取综合和公正的多学科方法 使用表达主要人载脂蛋白E的纯合靶向替换APOE2、APOE3和APOE4小鼠 异构体，在小鼠内源性ApoE启动子的控制下。APOE2小鼠有明显更长的 寿命比APOE3小鼠长，而APOE3小鼠的寿命又比APOE4小鼠长得多。这些老鼠 合理匹配人类载脂蛋白E基因/寿命数据。对人体对衰老的免疫反应进行建模 我们将使用表达人NOS2基因产物的双转基因小鼠。这一修改使硝酸 一氧化氮(NO)的产生和受NO调节的免疫活动，以更好地模拟人类的反应。我们的模特 包括雄性和雌性APOE2/HN(APOE2/2+小鼠NOS2-/-背景上的人NOS2)、APOE3/HN APOE4/HN小鼠，2龄，相当于人的中老年。小鼠的特征将是 认知行为电池，并用核磁共振来确定大脑网络的选择性脆弱性。我们的影像 测量将基于容量、血管灌注和扩散张量成像；并将提供 连接点和网络措施。RNA-Seq转录组学将鉴定基因的差异表达 与APOE基因相关的产品，在老化过程中。我们将使用一种无偏见的统计方法来绘制 衰老的行为和成像表型背后的分子途径。我们的努力将有助于建立 解释APOE基因型别对年龄和AD相关网络脆弱性影响的模型。我们 希望深入了解与衰老、AD、炎症和氧化磷酸化有关的途径。为了测试 模型中，我们将通过高脂肪/高糖饮食(模仿 西式饮食)。我们将结合转录组学评估行为和核磁共振表型，以及 通过通径分析确定饮食如何改变男性和女性APOE2/HN的预测结果， APOE3/HN和APOE4/HN小鼠。我们的研究将揭示APOE与 环境应激源使人变得脆弱，或在衰老过程中选择大脑回路具有韧性。

There is a rapid growth in the number of people living with Alzheimer’s disease, and only 25% get diagnosed; still we do not know its etiology or have effective treatments. To examine factors which contribute to switching from normal to pathological aging we focus on the APOE polymorphic alleles. The causes for increased risk, or conversely resilience, conferred by the major APOE alleles are not known. The APOE4/4 genotype is the main genetic risk for late onset Alzheimer’s disease (AD), and is associated with a 30-55% risk of developing mild cognitive impairment or AD by age 85, compared to 10-15% for the APOE3/3 genotype. In contrast APOE2 is under-represented in AD patients, and it has been associated with longevity. To help understand the mechanisms through which APOE genes and their products differentially modulate the brain and its circuits to switch from healthy to pathological aging, we will take an integrative and unbiased multi-disciplinary approach using homozygous targeted replacement APOE2, APOE3, and APOE4 mice expressing the major human APOE isoforms, under the control of the mouse endogenous ApoE promoter. APOE2 mice have a significantly longer lifespan than APOE3 mice, which in turn have a significantly longer lifespan than APOE4 mice. These mice reasonably match the human APOE-genotype/lifespan data. To model the human immune response to aging we will use double-transgenic mice that express human NOS2 gene products. This modification enables nitric oxide (NO) production and immune activity regulated by NO to better mimic the human response. Our models include male and female APOE2/HN (APOE2/2 + human NOS2 on a mouse Nos2-/- background), APOE3/HN, and APOE4/HN mice, at 2 ages corresponding to middle and old human age. Mice will be characterized with a cognitive behavioral battery, and with MRI to determine selective vulnerability of brain networks. Our imaging measures will be based on volume, vascular perfusion, and diffusion tensor imaging; and will provide connectomes and network measures. RNA-Seq transcriptomics will identify differential expression of gene products associated with APOE genotypes, during aging. We will use an unbiased statistical approach to map molecular pathways underlying the behavioral and imaging phenotypes for aging. Our efforts will help build models that explain the influence of APOE genotypes on age and AD associated network vulnerability. We expect to hone in on pathways involved in aging, AD, inflammation, and oxidative phosphorylation. To test models, we will add a stressor conferring risk in aging and AD, through a high fat/high sugar diet (mimicking the Western diet). We will assess behavioral, and MRI phenotypes, in conjunction with transcriptomics, and determine through pathway analysis how diet shifts the predicted outcomes in male and female APOE2/HN, APOE3/HN and APOE4/HN mice. Our research will reveal mechanisms through which APOE interacts with environmental stressors to confer vulnerability, or resilience to select brain circuits during aging.