Dietary protection against APOE4 phenotypes in aging and Alzheimer's

载脂蛋白E的ɛ4等位基因与加速衰老和死亡以及增加阿尔茨海默病(AD)的易感性有关。尽管APOE4、衰老和AD风险之间的因果联系仍未完全确定，但可能的机制包括调节能量代谢以及全身和神经炎性张力。我们最近的发现表明，营养方法，包括禁食模拟饮食(FMD)，在几种与年龄相关的条件下显示出抗衰老和保护作用。事实上，被确定为受FMD和相关营养干预有益调节的途径与被认为是APOE4、衰老和AD之间关系的途径重叠。在这个项目中，我们调查了饮食干预FMD将预防APOE4表型的中心假设，APOE4表型驱动年龄相关的认知障碍和AD的发病。我们将通过研究口蹄疫和相关饮食干预对人类载脂蛋白E基因携带者在AD转基因缺失和存在的情况下的系统和神经影响来研究这一假说。我们的研究将询问几种潜在的机制，这些机制被认为是载脂蛋白E和饮食之间基因X环境关系的基础，重点是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。目的1：饮食干预对APOE4相关衰老表型有保护作用吗？我们测试了这样的假设，即营养干预将改善老龄化和APOE4基因背景下的系统和神经结果。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有效性，评估一种类似空腹的线粒体衍生多肽在APOE基因中反映FMB保护作用的假设能力。目的2：饮食干预是否以载脂蛋白E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平行，但重点放在AD病理背景下的饮食和载脂蛋白E基因。这些研究将在雄性和雌性APOE3与APOE4AD小鼠身上进行，以确定潜在的性别差异，并在两个不同的年龄考虑预防和治疗的效果。目的3：饮食干预是否改善了与Ace、APOE4和AD相关的神经胶质表型？我们调查了这样一种假设，即饮食干预预防APOE4表型的主要机制是改善神经胶质细胞转录谱和功能。我们将质疑这样的假设，即APOE依赖差异的关键调节因子是TREM2-ApoE信号通路，该通路通过对小胶质细胞表型和代谢适应性的作用与AD风险有关。拟议研究的完成将产生临床前数据，这些数据定义了饮食、载脂蛋白E基因、性别、年龄和干预时机之间的相互作用和潜在机制，这些关系对于有效地临床翻译饮食策略以对抗认知下降和AD至关重要。

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.