Dietary protection against APOE4 phenotypes in aging and Alzheimer's

饮食对衰老和阿尔茨海默病中 APOE4 表型的保护作用

• 批准号: 10769123
• 负责人: CHRISTIAN J PIKE
• 金额: $ 99.64万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10769123
• 关键词: Acceleration; Age; Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Apolipoprotein E; Brain; Data; Diet; Dietary Intervention; Energy Metabolism; Environment; Exhibits; Fasting; Female; Genes; Genotype; Goals; Human; Impaired cognition; Impairment; In Situ; Inflammatory; Intervention; Ketones; Link; Metabolic; Methionine; Mitochondria; Mus; N-formylmethionylphenylalanine; Nutritional; Outcome; Outcome Measure; Pathogenesis; Pathology; Pathway interactions; Peptides; Phenotype; Prevention; Property; Regulation; Sex Differences; Shotguns; Signal Pathway; TREM2 gene; Testing; Transgenes; age related; anti aging; apolipoprotein E-3; clinical translation; combat; design; dietary; dietary control; efficacy testing; glial activation; improved; improved outcome; in vitro Model; lipid metabolism; lipidomics; male; metabolic fitness; middle age; mortality; mouse model; neural; novel; nutritional approach; pre-clinical; prevent; sex; transcriptomics

The ɛ4 allele of apolipoprotein E (APOE4) is associated with accelerated aging and mortality as well increased vulnerability to Alzheimer’s disease (AD). Although the causal links between APOE4, aging, and AD risk remain to be fully defined, candidate mechanisms include regulation of energy metabolism and systemic and neural inflammatory tone. Our recent findings demonstrate that nutritional approaches, including fasting mimicking diet (FMD), exhibit anti-aging and protective properties across several age-related conditions. Indeed, pathways identified to be beneficially regulated by FMD and related nutritional interventions overlap with pathways thought to underlie relationships among APOE4, aging, and AD. In this project, we investigate the central hypothesis that the dietary intervention FMD will protect against APOE4 phenotypes that drive age-related cognitive impairment and AD pathogenesis. We will investigate this hypothesis by studying systemic and neural effects of FMD and related dietary interventions across age in mice with human APOE genotypes both in the absence and presence of AD transgenes. Our studies will interrogate several potential mechanisms hypothesized to underlie gene X environment relationships between APOE and diet with emphases on brain energy metabolism and regulation of microglial activation profiles. We propose three aims. Aim 1: Do dietary interventions protects against APOE4-associated aging phenotypes? We test the hypothesis that nutritional interventions will improve systemic and neural outcomes in the contexts of aging and APOE4 genotype. Studies will test the ability of diet to prevent vs treat APOE4-associated phenotypes. We will test the efficacy of low methionine or high ketone diets assess the hypothesized abilities of a fasting-mimicking mitochondrial-derived peptide to mirror protective actions of FMB across APOE genotype. Aim 2: Do dietary interventions provide protection against Alzheimer pathology in an APOE-dependent manner? The second aim is conceptually parallel to Aim 1 but with a focus on diet and APOE genotype in the context of AD pathology. These studies will be conducted in male and female APOE3 vs APOE4 AD mice to determine potential sex differences and at two different ages to consider efficacies for both the prevention and treatment. Aim 3: Do dietary interventions improve glial phenotypes associated with again, APOE4, and AD? We investigate the hypothesis that the primary mechanism by which dietary interventions protect against APOE4 phenotypes is improvement in glial transcriptomic profiles and functions. We will interrogate the hypothesis that a key regulator of APOE-dependent differences is the TREM2-ApoE signaling pathway, which is linked to AD risk via actions on microglial phenotype and metabolic fitness. Completion of the proposed studies will yield preclinical data that define the interactions and underlying mechanisms among diet, APOE genotype, sex, age, and intervention timing, relationships that are essential to the effective clinical translation of dietary strategies to combat cognitive decline and AD.

载脂蛋白E （APOE4）的等位基因与加速衰老和死亡率以及阿尔茨海默病（AD）易感性增加有关。尽管APOE4、衰老和AD风险之间的因果关系尚未完全确定，但候选机制包括能量代谢调节和全身和神经炎症张力。我们最近的研究结果表明，营养方法，包括禁食模拟饮食（FMD），在几种与年龄相关的疾病中表现出抗衰老和保护特性。事实上，口蹄疫和相关营养干预所确定的有益调节通路与APOE4、衰老和AD之间关系的通路重叠。在本项目中，我们研究了饮食干预FMD将保护APOE4表型的中心假设，APOE4表型驱动年龄相关的认知障碍和AD发病机制。我们将通过研究人类APOE基因型小鼠在没有和存在AD转基因的情况下，口蹄疫和相关饮食干预对整个年龄的系统和神经的影响来研究这一假设。我们的研究将探究APOE与饮食之间的基因X环境关系的几种潜在机制，重点关注大脑能量代谢和小胶质细胞激活谱的调节。我们提出了三个目标。目标1：饮食干预是否可以预防apoe4相关的衰老表型？我们测试了营养干预将改善衰老和APOE4基因型背景下的系统和神经结果的假设。研究将测试饮食预防和治疗apoe4相关表型的能力。我们将测试低蛋氨酸或高酮饮食的功效，评估模拟禁食的线粒体衍生肽在APOE基因型中反映FMB保护作用的假设能力。目标2：饮食干预是否以apoe依赖的方式提供对阿尔茨海默病的保护？第二个目标在概念上与目标1相似，但重点关注AD病理背景下的饮食和APOE基因型。这些研究将在雄性和雌性APOE3与APOE4 AD小鼠中进行，以确定潜在的性别差异，并在两个不同的年龄进行研究，以考虑预防和治疗的效果。目标3：饮食干预是否能改善与APOE4和AD相关的神经胶质表型？我们研究了一种假设，即饮食干预保护APOE4表型的主要机制是改善神经胶质转录组谱和功能。我们将质疑apoe依赖性差异的关键调节因子是TREM2-ApoE信号通路的假设，该信号通路通过对小胶质细胞表型和代谢适应性的作用与AD风险相关。这些研究的完成将产生临床前数据，以确定饮食、APOE基因型、性别、年龄和干预时间之间的相互作用和潜在机制，这些关系对于有效临床转化饮食策略以对抗认知能力下降和AD至关重要。