Dietary protection against APOE4 phenotypes in aging and Alzheimer's

载脂蛋白E（APOE 4）的等位基因与加速衰老和死亡以及增加对阿尔茨海默病（AD）的易感性有关。虽然APOE 4、衰老和AD风险之间的因果关系仍有待充分确定，但候选机制包括能量代谢调节以及全身和神经炎症张力。我们最近的研究结果表明，营养方法，包括禁食模仿饮食（FMD），在几种与年龄相关的疾病中表现出抗衰老和保护作用。事实上，被确定为FMD和相关营养干预有益调节的途径与被认为是APOE 4、衰老和AD之间关系的基础的途径重叠。在这个项目中，我们研究了一个中心假设，即饮食干预FMD将防止APOE 4表型驱动年龄相关的认知障碍和AD发病机制。我们将研究这一假设，通过研究FMD和相关的饮食干预在不同年龄段的人APOE基因型小鼠在AD转基因的存在和不存在下的全身和神经的影响。我们的研究将询问几个潜在的机制假设为基础的基因X的环境之间的关系APOE和饮食与脑能量代谢和调节小胶质细胞激活配置文件的重点。我们提出三个目标。目的1：饮食干预是否能预防APOE 4相关的衰老表型？我们测试的假设，即营养干预措施将改善系统和神经的结果在老龄化和APOE 4基因型的背景下。研究将测试饮食预防与治疗APOE 4相关表型的能力。我们将测试低甲硫氨酸或高酮饮食的功效，评估模拟禁食的尿道衍生肽在APOE基因型中反映FMB保护作用的假设能力。目的2：饮食干预是否以APOE依赖的方式提供对阿尔茨海默病病理学的保护？第二个目标在概念上与目标1相似，但重点是AD病理学背景下的饮食和APOE基因型。这些研究将在雄性和雌性APOE 3与APOE 4 AD小鼠中进行，以确定潜在的性别差异，并在两个不同年龄进行，以考虑预防和治疗的有效性。目的3：饮食干预是否能改善与AD、APOE 4相关的胶质细胞表型？我们调查的假设，即饮食干预保护APOE 4表型的主要机制是改善胶质细胞转录谱和功能。我们将询问这样的假设，即APOE依赖性差异的关键调节因子是TREM 2-ApoE信号通路，其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。完成拟议的研究将产生临床前数据，定义饮食，APOE基因型，性别，年龄和干预时机之间的相互作用和潜在机制，这些关系对于有效临床翻译饮食策略以对抗认知衰退和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.