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 等位基因是晚发性心脏病的主要遗传风险因素之一阿尔茨海默病 (AD) 是脑血管 (CV) 功能障碍的重要诱因，现在被认为是 AD 病理学的一个主要组成部分。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，并且先于大脑淀粉样蛋白和 tau 蛋白 CV系统调节葡萄糖向大脑的转运以支持神经系统。随着年龄的增长，带有 E4 等位基因的个体的能力会出现缺陷。将营养物质输送到大脑，最终迫使神经元执行脂肪酸 (FA) 如果在神经元中进行脂肪酸代谢是有害的，因为它会促进新陈代谢。 FA代谢过程需要左旋肉碱来运输FA。酰基肉碱 (CAR) 进入线粒体（左旋肉碱生物能学）。我们最近的研究强调了 AD 系统，表明左旋肉碱生物能缺陷是存在于 E4 携带者中并与 AD 中的 CV 病理相关。将葡萄糖传感与左旋肉碱乙酰辅酶A羧化酶（ACC）联系起来的途径通过靶向替换小鼠，改变小鼠脑血管的生物能学具有人类 APOE4 (E4-TR) 的 APOE 和具有人类 APOE4 同工型的 AD 小鼠模型。因此，我们认为 E4 会破坏 CV 细胞内的左旋肉碱生物能学，从而与营养物质向脑实质的运输受损相对应，这会增加。神经元内对左旋肉碱生物能的依赖，导致氧化应激和为了检验这个假设，我们首先要确定大脑是否存在炎症。内皮细胞 (BEC) 或壁细胞经历左旋肉碱生物能的改变，然后我们将确定两种细胞内 APOE 基因型随年龄的差异影响。确定通过抑制 BEC 中的 ACC 来促进左旋肉碱生物能途径是否有帮助恢复脑实质的营养平衡拟议的研究将提供新的内容。深入了解 ACC 介导的左旋肉碱生物能学在开发治疗方法中的作用专门针对 E4 运营商的策略，他们的体验明显更高脑血管疾病负担与 AD 发病机制相关。