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，影响着全世界 5000 万人。越来越多的人认识到，除了淀粉样蛋白和 tau 蛋白外，还有其他因素会导致 AD 的病因复杂且异质，在这方面，最近的研究表明大脑生物能。缺陷和异常的脂质代谢改变了大脑的环境，使其更容易受到与年龄相关的损害肉碱和酰基会增加大脑对 AD 的易感性，因此肉碱对于 AD 至关重要。中枢神经系统（CNS）生物能学由于其在线粒体脂肪酸氧化中的作用患有该疾病的受试者在幼年时就观察到大脑的能量需求不足。载脂蛋白 E (APOE) ε4 等位基因，是大多数迟发性 AD 最重要的遗传风险因素拟议的工作将探讨 APOE ε4 在肉碱和酰基肉碱介导中的影响。 AD 发病机制中的生物能缺陷。我们最近观察到肉碱，一种肉碱代谢物三甲胺 N-氧化物 (TMAO) 和 AD 患者的血液和大脑中的酰基肉碱水平发生了改变。 AD 临床前或早期阶段的 TMAO 水平升高，中链酰基肉碱 (MCA) 水平升高。在 ε4 携带者的大脑和血液中检测到这些数据，反映了不完全的脂肪酸氧化。结合 ε4 携带者大脑中葡萄糖代谢低下的现有证据，表明生物能量缺陷可能是 AD 的早期事件，因此我们追寻 APOE ε4 依赖性缺陷。外周肉碱和酰基肉碱向大脑的转运及其在外周或体内的代谢大脑会导致大脑生物能量缺陷，从而使大脑容易受到 AD 病理的影响。首先从神经病理学角度表征大脑和血液中的异常肉碱和酰基肉碱谱诊断为 AD 患者并在 AD 小鼠模型中检查 APOE 基因型对 AD 的影响我们将检查外周给药是否稳定。同位素标记的肉碱和酰基肉碱在 AD 小鼠中的运输和代谢存在差异具有 5 x AD 突变和用人类 APOE 基因靶向替换小鼠 APOE 的模型我们还将确定这些变化是否发生在疾病发作之前或发生时。这些研究将阐明 APOE ε4 是否有助于运输和 tau 病理学。外周肉碱和酰基肉碱的代谢缺陷，并确定开发的新途径 AD 的治疗策略，特别是对于患有 AD 的高风险的 ε4 阳性个体。