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

阿尔茨海默病是一种神经退行性疾病，影响全球5000万人。是 越来越多的人认识到，除了淀粉样蛋白和tau蛋白之外，还有其他因素有助于 AD的病因复杂多样。在这方面，最近的调查表明，大脑生物能量 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有关的损伤 从而增加大脑对AD的易感性。肉毒碱和酰基肉毒碱是至关重要的 中枢神经系统（CNS）生物能量学，因为它们在线粒体中的脂肪酸氧化中的作用， 大脑的能量需求。在患有糖尿病的受试者中，在早期就观察到生物能量缺陷。 载脂蛋白E（apolipoprotein E，APOE）ε4等位基因是大多数迟发性AD最重要的遗传危险因素 例这项工作将探讨载脂蛋白E ε4在肉毒碱和酰基肉毒碱介导的 AD发病机制中的生物能量缺陷。 我们最近观察到，肉毒碱，肉毒碱代谢产物三甲胺N-氧化物（TMAO）和 在AD患者的血液和脑中，酰基肉毒碱水平发生改变。我们还表明，ε4载流子在 AD的临床前或早期阶段具有升高的TMAO水平。中链酰基肉毒碱（MCA）升高 在ε4携带者的脑和血液中检测到，反映了不完全的脂肪酸氧化。这些数据， 结合ε4携带者大脑中葡萄糖代谢低下的现有证据，表明 生物能量缺乏可能是AD的早期事件。因此，我们假设，APOE ε4依赖性缺陷， 外周肉毒碱和酰基肉毒碱向脑的运输以及它们在外周或脑内的代谢 大脑导致大脑生物能缺陷，这使得大脑易受AD病理的影响。我们将 首先从神经病理学上描述脑和血液中的异常肉毒碱和酰基肉毒碱谱 诊断的AD患者和AD小鼠模型中，以检查APOE基因型对AD患者的影响。 肉毒碱/酰基肉毒碱与AD的关系我们将检查外周给药是否稳定 同位素标记的肉毒碱和酰基肉毒碱在AD小鼠中的差异转运和代谢 具有5 × AD突变和用人APOE基因靶向置换鼠APOE的模型 同种型（EFAD小鼠）。我们还将确定这些变化是否发生在发病前或发病时。 淀粉样蛋白和tau病理学。这些研究将阐明APOE ε4是否有助于运输和 外周肉毒碱和酰基肉毒碱的代谢缺陷，并确定新的途径， AD的治疗策略，特别是对于处于AD高风险中的ε4阳性个体。

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.