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The effects of APOE4 on carnitine/acylcarnitine mediated bioenergetic deficits in Alzheimer's disease

APOE4 对肉碱/酰基肉碱介导的阿尔茨海默病生物能缺陷的影响

基本信息

批准号：
10370296
负责人：
Laila Abdullah
金额：
$ 16.2万
依托单位：
ROSKAMP INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10370296
关键词：
Affect Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapy American Amyloid Apolipoprotein E Bioenergetics Biological Factors Blood Brain Carnitine Cerebrospinal Fluid Chronic Complex Data Development Disease Drug Targeting Etiology Event Fatty Acids Generations Genetic Genotype Glucose Human Impaired cognition Impairment Individual Inflammation Insulin Resistance Investigation Late Onset Alzheimer Disease Lead Mediating Metabolism Mitochondria Mus Mutation Nerve Degeneration Neuraxis Pathogenesis Pathology Pathway interactions Peripheral Persons Pharmaceutical Preparations Process Protein Isoforms Role Senile Plaques Stable Isotope Labeling Waste Products Work acylcarnitine age related brain dysfunction deprivation dietary fatty acid oxidation genetic risk factor high risk hyperphosphorylated tau insight lipid metabolism lipid transport mouse model novel strategies novel therapeutic intervention oxidation pre-clinical prevent tau Proteins treatment strategy trimethyloxamine

项目摘要

Alzheimer’s disease is a neurodegenerative condition which affects 50 million people worldwide. It is increasing being recognized that, in addition to amyloid and tau, there are other factors which contribute to the complex and heterogenous etiology of AD. In that regard, recent investigations show that brain bioenergetic deficits and abnormal lipid metabolism alter the brain’s milieu, making it more susceptible to age-related insults and thereby increasing the brain’s vulnerability to developing AD. Carnitine and acylcarnitines are critical for central nervous system (CNS) bioenergetics due to their role in fatty acids oxidation in mitochondria for the brain’s energy requirements. Bioenergetic deficits are observed at an early age in subjects with the apolipoprotein E (APOE) ε4 allele, which is the most important genetic risk factor for majority of late-onset AD cases. The proposed work will explore the influence of APOE ε4 in carnitine- and acylcarnitine-mediated bioenergetic deficits in the pathogenesis of AD. We recently observed that carnitine, a carnitine metabolite trimethylamine N-oxide (TMAO) and acylcarnitine levels are altered in the blood and brains of AD patients. We also show that ε4 carriers at preclinical or early stages of AD have elevated levels of TMAO. Elevated medium chain acylcarnitine (MCA) were detected in the brain and blood of ε4 carriers, reflecting an incomplete fatty acid oxidation. These data, together with the existing evidence of glucose hypometabolism in the brains of ε4 carriers, suggest that bioenergetic deficit may be an early event in AD. We therefore hypothesize that APOE ε4 dependent deficits in the transport of peripheral carnitine and acylcarnitines to the brain and in their metabolism in the periphery or in the brain contribute to the brain bioenergetic deficits which make the brain vulnerable to AD pathology. We will first characterize abnormal carnitine and acylcarnitine profiles in the brain and blood of neuropathologically diagnosed AD patients and in AD mouse models to examine the influence of APOE genotypes on the relationship between carnitine/acylcarnitines and AD. We will examine if peripherally administered stable isotope labeled carnitine and acylcarnitines are differentially transported and metabolized in an AD mouse model with 5 x AD mutations and with genetic targeted replacement of murine APOE with human APOE isoforms (EFAD mice). We will also determine whether these changes occur prior to or with the onset of amyloid and tau pathologies. These studies will clarify whether APOE ε4 contributes to both transport and metabolism deficiencies of peripheral carnitine and acylcarnitines and identify new avenues for developing treatment strategies for AD, particularly for ε4 positive individuals who are at a high risk of developing AD.

阿尔茨海默病是一种神经退行性疾病，影响着全球5000万人。它是越来越多的人认识到，除了淀粉样蛋白和tau外，还有其他因素导致阿尔茨海默病的病因复杂且异质性。在这方面，最近的研究表明，大脑生物能量缺陷和异常的脂肪代谢改变了大脑的环境，使它更容易受到与年龄有关的侮辱从而增加大脑对阿尔茨海默病的易感性。肉碱和酰基肉碱对中枢神经系统(CNS)生物能量学在线粒体脂肪酸氧化中的作用大脑的能量需求。生物能量缺乏在早期就被观察到。载脂蛋白Eε4等位基因是大多数晚发性AD最重要的遗传危险因素案子。这项拟议的工作将探索载脂蛋白Eε4在肉碱和酰基肉碱介导的过程中的影响阿尔茨海默病发病机制中的生物能量缺乏。我们最近观察到肉碱，肉碱的代谢物三甲胺N-氧化物(TMAO)和 AD患者血液和大脑中的酰肉碱水平会发生变化。我们还表明，ε4运营商在临床前或早期AD患者血清TMAO水平升高。提升中链酰基肉碱(MCA) 在ε4携带者的脑和血液中检测到，反映了脂肪酸的不完全氧化。这些数据，再加上ε4携带者大脑中葡萄糖代谢不足的现有证据，表明生物能量缺乏可能是AD的早期事件。因此，我们假设APOEε4依赖于外周肉碱和乙酰肉碱到大脑的运输及其在外周或外周代谢中的作用大脑造成了大脑的生物能量缺陷，使大脑容易受到AD病理的影响。我们会首次从神经病理学的角度描述了脑和血液中肉碱和乙酰肉碱的异常图谱在诊断为AD的患者和AD小鼠模型中检查APOE基因对肉碱/酰肉碱与阿尔茨海默病的关系我们将检查外周给药是否稳定同位素标记肉碱和酰肉碱在AD小鼠体内的不同转运和代谢 5 x AD突变和人载脂蛋白E基因靶向替换小鼠载脂蛋白E的模型异构体(EFAD小鼠)。我们还将确定这些变化是发生在淀粉样蛋白和tau病理。这些研究将澄清APOEε4是否对运输和外周肉碱和酰基肉碱的代谢缺陷及开发新途径阿尔茨海默病的治疗策略，特别是针对ε4阳性的高危人群。