Brain networks in mouse models of aging

小鼠衰老模型中的大脑网络

• 批准号: 10641887
• 负责人: Alexandra Badea
• 金额: $ 74.34万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10641887
• 关键词: Abeta clearance; Address; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Animal Model; Apolipoprotein E; Apoptosis; Atrophic; Behavior; Behavior assessment; Behavioral; Biological; Biological Markers; Blood Vessels; Brain; Brain imaging; Brain region; Caregivers; Cerebrovascular Circulation; Clinical; Cognitive; Cognitive deficits; Data; Degenerative Disorder; Diagnosis; Diet; Dietary Intervention; Diffusion Magnetic Resonance Imaging; Disease; Disease Marker; Endosomes; Environment; Environmental Risk Factor; Etiology; Fatty acid glycerol esters; Female; Genes; Genetic; Genetic Models; Genetic Risk; Genotype; Human; IGF1 gene; IL6 gene; Image; Immune; Immune response; Inflammation; Injury; Intervention; Late Onset Alzheimer Disease; Learning; Link; Literature; Longevity; Magnetic Resonance Imaging; Maps; Measures; Mediating; Memory; Mitochondria; Modeling; Modification; Molecular; Monitor; Mus; Myelin; NOS2A gene; Nerve Degeneration; Nitric Oxide; Outcome; Oxidative Phosphorylation; Pathology; Pathway Analysis; Pathway interactions; Performance; Perfusion; Persons; Phenotype; Physiological; Population; Process; Production; Property; Protein Isoforms; Quality of life; Regulation; Research; Resolution; Risk; Role; SIRT1 gene; Source; Statistical Data Interpretation; Synapses; TNF gene; Temporal Lobe; Testing; Tissue-Specific Gene Expression; Transgenic Mice; abeta accumulation; age related; aging brain; apolipoprotein E-3; apolipoprotein E-4; behavioral phenotyping; biomarker signature; brain volume; conditioned fear; connectome; cost; design; differential expression; early detection biomarkers; effective therapy; environmental stressor; gene product; genetic signature; genetic variant; high risk; human model; in vivo; innovation; insight; interdisciplinary approach; lipid metabolism; male; mild cognitive impairment; model building; morris water maze; mouse model; outcome prediction; pathological aging; predictive modeling; promote resilience; promoter; rapid growth; resilience; response; sex; stressor; sugar; tau Proteins; tau mutation; tau-1; transcriptome sequencing; transcriptomics; western diet; white matter

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.

患有阿尔茨海默病的人数迅速增长，只有25%的人得到诊断; 我们至今仍不知道其病因或有有效的治疗方法。检查导致转换的因素 从正常衰老到病理衰老，我们关注APOE多态性等位基因。风险增加的原因，或 相反，由主要的APOE等位基因赋予的弹性尚不清楚。APOE 4/4基因型是主要的 阿尔茨海默病（AD）的遗传风险，并与30-55%的风险发展为轻度阿尔茨海默病（AD）相关。 认知障碍或AD，相比之下，APOE 3/3基因型为10-15%。APOE 2是 在AD患者中代表性不足，并且与长寿相关。帮助理解 APOE基因及其产物差异调节大脑及其回路的机制， 由健康老化转为病理老化，我们会采取综合和不偏不倚的多学科研究方法 使用表达主要人APOE的纯合靶向替代APOE 2、APOE 3和APOE 4小鼠， 同种型，在小鼠内源性ApoE启动子的控制下。APOE 2小鼠具有显著更长的 APOE 3小鼠的寿命比APOE 4小鼠长，而APOE 3小鼠的寿命又比APOE 4小鼠长得多。这些小鼠 合理匹配人APOE基因型/寿命数据。模拟人类对衰老的免疫反应 我们将使用表达人NOS 2基因产物的双转基因小鼠。这种改变使硝酸 氧化物（NO）的产生和由NO调节的免疫活性，以更好地模拟人类反应。我们的模型 包括雄性和雌性APOE 2/HN（小鼠Nos 2-/-背景上APOE 2/2 +人NOS 2）、APOE 3/HN APOE 4/HN小鼠，在2个年龄段（相当于人的中、老年年龄）。小鼠的特征在于 认知行为电池，并与MRI确定大脑网络的选择性脆弱性。我们的成像 测量将基于容积、血管灌注和弥散张量成像;并将提供 连接体和网络测量。RNA-Seq转录组学将鉴定基因的差异表达 与APOE基因型相关的产物。我们将使用无偏的统计方法来绘制 衰老的行为和成像表型的分子途径。我们的努力将有助于建立 解释APOE基因型对年龄和AD相关网络脆弱性的影响的模型。我们 希望能深入研究衰老、AD、炎症和氧化磷酸化的途径。测试 模型，我们将通过高脂肪/高糖饮食（模仿 西方饮食）。我们将结合转录组学评估行为和MRI表型， 通过途径分析确定饮食如何改变男性和女性APOE 2/HN的预测结果， APOE 3/HN和APOE 4/HN小鼠。我们的研究将揭示APOE与 环境压力因素赋予脆弱性，或在衰老过程中选择大脑回路的弹性。