Neuropathologic-Epidemiological Study of Metallomics and Alzheimer's Disease

项目总结 金属组学与阿尔茨海默病的神经病理学-流行病学研究(RF1AG054057) 首次证明在人脑中直接测量的促氧化剂铁与 阿尔茨海默病患者认知功能减退。在这项拟议的延续中，我们建议进一步 这些研究旨在解决大脑铁升高的潜在机制，铁介导的损伤的易感性， 以及随之而来的衰退。支持我们假设的是最近发现的程序性死亡途径， 铁性下垂，通过铁依赖的过氧化作用导致突触和细胞膜的破坏 某些脂类。强劲的初步数据支持这些目标。在这次竞争性的续订中，我们建议测试 假设(1)膳食脂肪和脑脂有助于脑内铁的升高；以及(2)铁相互作用 使用脑脂来促进脂质过氧化，导致中毒性脑损伤(通过铁性下垂)，神经元丢失，以及 最终加速了认知和运动能力的衰退。我们建议使用新的方法， 使用先进的方法结合(氧化的)脂质组学(即靶向和氧化的脂质组学和 免疫辅助串联激光消融/电感耦合等离子体质谱(MALDI/ICPMS)定位铁和脂类介导的神经变性 认知和运动脑区域。我们将扩大饮食研究，并利用丰富的临床和 来自Rush Memory and Aging Project的病理数据。总括而言，我们建议收集以下新数据： 脑脂，将铁和饮食脂肪的数据增加到850个大脑的目标。在目标1中，我们将检验假设 饮食脂肪摄入量与大脑脂肪成分和铁含量有关；大脑脂肪成分是 与脑铁含量有关；并使用先进技术绘制和测试它们之间的关系 分层的皮质。在目标2中，我们建议检测氧化脂质并检验脂质过氧化是 与脑铁、阿尔茨海默氏症和认知功能减退有关。我们还将调查脂类是否 过氧化物质介导AD中铁相关的认知功能下降。在目标3中，我们将测定脑铁和 (氧化)脑运动区的脂质含量，并检验区域脑铁与 脂质成分与运动功能下降和运动病理(路易体、血管、AD等)有关。在……里面 老年人。在每个目标中，我们都将调查载脂蛋白ε4、阿尔茨海默氏病的关系有何不同 诊断和性行为。总体而言，这些研究有可能揭示铁、脂类 (饮食和大脑)和载脂蛋白ε4会增加衰老和AD患者的认知和运动能力下降。这些研究具有 有可能揭示新的和有针对性的生物途径。

PROJECT SUMMARY The project Neuropathologic-Epidemiological Study of Metallomics and Alzheimer's Disease (RF1AG054057) demonstrated for the first time that pro-oxidant iron directly measured in human brain is strongly associated with cognitive decline in older persons with AD pathology. In this proposed continuation, we propose to further these studies to resolve mechanisms underlying brain iron elevation, susceptibility to iron-mediated damage, and resultant decline. Underpinning our hypothesis is the recently discovered programmed death pathway, ferroptosis, which causes destruction of synaptic and cellular membranes by iron dependent peroxidation of certain lipids. Strong preliminary data supports these aims. In this competive renewal, we propose to test the hypotheses that (1) dietary fat and brain lipids contribute to the elevation of brain iron; and (2) iron interacts with brain lipids to promote lipid peroxidation, resulting in toxic brain injury (via ferroptosis), neuronal loss, and ultimately accelerated cognitive and motor decline in aging. We propose to use novel methodologies, incorporating (oxidized) lipidomics using advanced methodologies (i.e. targeted and oxidized lipidomics and immune-assisted, tandem Laser Ablation MALDI/ICP-MS) to map iron and lipid-mediated neurodegeneration in cognitive and motor brain regions. We will expand dietary studies, and leverage a rich resource of clinical and pathologic data available from Rush Memory and Aging Project. Overall, we propose to collect new data on brain lipids, increase data on iron and dietary fats to goal of 850 brains. In Aim 1, we will test the hypotheses that dietary fat intake is associated with brain lipid composition and iron content; that brain lipid composition is associated with brain iron content; and use advanced technology to map and test their relationship across the layered cortex. In Aim 2, we propose to detect oxidized lipids and test the hypotheses that lipid peroxidation is associated with brain iron, Alzheimer’s pathology, and cognitive decline. We also will investigate whether lipid peroxides mediate cognitive decline associated with iron in AD. In Aim 3 we will determine brain iron and (oxidized) lipid content in brain motor regions and test the hypothesis that regional brain iron is associated with lipid composition and with motor function and decline and motor pathology (Lewy body, vascular, AD, etc.) in older persons. In each aim, we will investigate how relationships differ by APOE ε4, Alzheimer’s pathologic diagnosis and sex. Overall, these studies have the potential to uncover new mechanisms by which iron, lipids (diet and brain), and APOE ε4 increase cognitive and motor decline in aging and AD. These studies have the potential to reveal new and targetable biologic pathways.