Cerebrovascular contributions to APOE4-mediated brain bioenergetic deficits in Alzheimer's disease

载脂蛋白E（apolipoprotein E，APOE）E4等位基因是晚发型糖尿病的主要遗传危险因素之一 阿尔茨海默病（AD）是脑血管（CV）功能障碍的重要原因， 其现在被认为是AD病理学的主要组成部分。AD研究新进展 这表明E4携带者在向大脑供应葡萄糖方面具有年龄依赖性的脆弱性， 这与较低的葡萄糖代谢相对应，并先于脑淀粉样蛋白和tau蛋白 病理学CV系统调节葡萄糖转运到大脑，以支持神经元 生物能量学随着年龄的增长，具有E4等位基因的个体在以下能力上出现缺陷： 将营养物质输送到大脑，最终迫使神经元执行脂肪酸（FA） 新陈代谢.脂肪酸代谢是有害的，如果在神经元中进行，因为它可以有助于 氧化应激FA代谢的过程需要L-肉毒碱来转运FA， 酰基肉毒碱（CAR）进入线粒体（L-肉毒碱生物能量学）。这一点的重要性 我们最近的研究表明，L-肉碱-生物能赤字是 存在于E4携带者中，并与AD中的CV病理学相关。我们的动物研究表明 将葡萄糖传感与乙酰辅酶A羧化酶（ACC）连接起来的L-肉毒碱- 在小鼠的血管系统中，通过靶向替换小鼠的细胞因子来改变生物能量学。 APOE与人APOE 4（E4-TR）和AD小鼠模型与人APOE 4同种型。 因此，我们假设E4破坏CV细胞内的L-肉碱生物能量学， 与营养物质向脑实质的运输受损相对应。这增加了 依赖于L-肉毒碱-神经元内的生物能量学，并有助于氧化应激， 脑部炎症为了验证这一假设，我们将首先确定大脑是否 内皮细胞（BEC）或壁细胞经历改变的L-肉毒碱生物能量学， 确定两种细胞内APOE基因型随年龄变化的差异影响。然后我们将 确定是否通过抑制BEC中的ACC来促进L-肉碱生物能量学途径将有助于 恢复脑实质的营养平衡。这些研究将提供新的 深入了解ACC介导的L-肉碱生物能量学在开发治疗药物中的作用 特别针对E4携带者的战略，他们的经历要高得多。 脑血管疾病负担与AD发病机制相关。

The apolipoprotein E (APOE) E4 allele is one of the major genetic risk factors for late-onset Alzheimer’s disease (AD) and an important contributor to cerebrovascular (CV) dysfunction, which is now considered a major component of AD pathology. Recent advances in AD research suggest that E4 carriers have an age-dependent vulnerability in supplying glucose to the brain, which corresponds with lower glucose metabolism and precedes brain amyloid and tau pathologies. The CV system regulates glucose transport to the brain to support neuronal bioenergetics. With age, individuals with the E4 allele experience deficits in their ability to transport nutrients to the brain, which eventually, forces neurons to perform fatty acid (FA) metabolism. Fatty acid metabolism is harmful if performed in neurons as it can contribute to oxidative stress. The process of FA metabolism requires L-carnitine for transporting FA as acylcarnitines (CAR) into mitochondria (L-carnitine bioenergetics). The importance of this system in AD is highlighted by our recent study showing that L-carnitine-bioenergetic deficits are present in E4 carriers and correlate with CV pathologies in AD. Our animal studies herein show pathways that link glucose sensing with acetyl-CoA carboxylase (ACC) for L-carnitine- bioenergetics are altered in the cerebrovasculature of mice with targeted replacement of mouse APOE with human APOE4 (E4-TR) and AD mouse models with the human APOE4 isoform. We, therefore, hypothesize that E4 disrupts L-carnitine-bioenergetics within the CV cells, which corresponds with impaired transport of nutrients to the brain parenchyma. This increases the reliance on L-carnitine-bioenergetics within neurons and contributes to oxidative stress and inflammation in the brain. To test this hypothesis, we will first determine whether brain endothelial cells (BEC) or mural cells experience altered L-carnitine bioenergetics and determine the differential impact of APOE genotypes within both cells with age. We will then determine if boosting L-carnitine bioenergetics pathways by inhibiting ACC in BEC will help restore nutrient balance in the brain parenchyma. The proposed studies will provide novel insights into the role of ACC-mediated L-carnitine bioenergetics for developing therapeutic strategies specifically targeting E4 carriers, who experience a significantly higher cerebrovascular disease burden associated with AD pathogenesis.