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

脑血管对 APOE4 介导的阿尔茨海默病脑生物能缺陷的影响

基本信息

批准号：
10739352
负责人：
Laila Abdullah
金额：
$ 44.95万
依托单位：
ROSKAMP INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739352
关键词：
Acetyl-CoA Carboxylase Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Animals Apolipoprotein E Bioenergetics Biological Markers Brain Cells Cerebrovascular Disorders Cerebrovascular system Chemicals Disease Energy Supply Equilibrium Exhibits Failure Fatty Acids Functional disorder Gene Silencing Genotype Glucose Human Impairment Individual Inflammation Ketone Bodies Ketones Late Onset Alzheimer Disease Levocarnitine Link Lipids Mediating Metabolism Mitochondria Molecular Mus Mutation Neurofibrillary Tangles Neurons Nutrient Oxidative Stress Pathogenesis Pathology Pathway interactions Pericytes Persons Play Process Protein Isoforms Research Risk Role Senile Plaques Smooth Muscle Myocytes Stable Isotope Labeling System Testing Therapeutic Time Work acylcarnitine age related aging brain apolipoprotein E-4 brain endothelial cell brain parenchyma burden of illness cell age cerebrovascular cerebrovascular pathology experience fatty acid metabolism fatty acid oxidation fatty acid transport flexibility genetic risk factor glucose metabolism glucose transport glucose uptake hyperphosphorylated tau improved in vivo inhibitor insight lipid metabolism long chain fatty acid mouse model neuroinflammation novel oxidation pre-clinical synaptic function tau Proteins

项目摘要

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.

载脂蛋白E（APOE）E4等位基因是晚发的主要遗传危险因素之一阿尔茨海默氏病（AD）和引起脑血管（CV）功能障碍的重要因素，现在被认为是AD病理学的主要组成部分。广告研究的最新进展表明E4载体在向大脑供应葡萄糖时具有年龄依赖性脆弱性，它与较低的葡萄糖代谢相对应，并且先于脑淀粉样蛋白和TAU 病理。 CV系统调节葡萄糖转运到大脑以支持神经元生物能学。随着年龄的增长，具有E4等位基因的个人在能力方面经历了防御能力将养分运送到大脑，这有时会迫使神经元执行脂肪酸（FA）代谢。如果在神经元中进行脂肪酸代谢有害，因为它可能有助于氧化应激。 FA代谢的过程需要L-肉碱运输FA作为线粒体（L-肉碱生物能学）进入线粒体。这一点的重要性我们最近的研究表明，广告中的系统是L-肉碱生物能定义的存在于E4载体中，并与AD中的CV病理相关。我们这里的动物研究表明将葡萄糖传感与乙酰辅酶A羧化酶（ACC）联系起来的途径在小鼠的脑脊椎管中改变了生物能学，靶向鼠标的靶向 APOE与人APOE4（E4-TR）和AD小鼠模型具有人类APOE4同工型。因此，我们假设E4破坏了CV细胞中的L-肉碱生物能，这些生物能量与营养物质到脑实质的运输受损相对应。这增加了依赖神经元内L-肉碱生物能学，并有助于氧化应激和大脑炎症。为了检验这一假设，我们将首先确定是否大脑内皮细胞（BEC）或壁画细胞经历L-肉碱生物能的改变，并且确定随着年龄的增长，确定两个细胞中APOE基因型的差异影响。然后我们会确定通过在BEC中抑制ACC来增强L-肉碱生物能途径是否有帮助恢复大脑实质中的营养平衡。拟议的研究将提供新颖洞悉ACC介导的L-肉碱生物能量在开发治疗方面的作用专门针对E4承运人的策略，他们经历了明显更高的策略脑血管疾病与AD发病机理相关。