Neuropathologic-Epidemiological Study of Metallomics and Alzheimer's Disease

项目摘要 金属组学和阿尔茨海默病的神经病理学-流行病学研究项目（RF 1AG 054057） 首次证明了在人脑中直接测量的促氧化铁与 老年AD患者的认知能力下降。在这一拟议的延续中，我们建议进一步 这些研究旨在解决脑铁升高的潜在机制，对铁介导的损伤的易感性， 以及随之而来的衰落。支持我们假设的是最近发现的程序性死亡途径， 铁凋亡，通过铁依赖性过氧化反应导致突触和细胞膜破坏， 某些脂类强有力的初步数据支持这些目标。在这次竞争性的更新中，我们建议测试 假设（1）膳食脂肪和脑脂质有助于脑铁的升高;（2）铁相互作用 与脑脂质一起促进脂质过氧化，导致毒性脑损伤（通过铁凋亡），神经元丢失， 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， 使用先进的方法学结合（氧化）脂质组学（即靶向和氧化脂质组学， 免疫辅助，串联激光消融MALDI/ICP-MS），以绘制铁和脂质介导的神经变性， 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 病理数据可从拉什记忆和衰老项目。总体而言，我们建议收集以下方面的新数据： 大脑脂质，增加铁和膳食脂肪的数据，以达到850个大脑的目标。在目标1中，我们将检验假设 膳食脂肪摄入与脑脂质组成和铁含量相关;脑脂质组成 与大脑铁含量相关;并使用先进的技术来绘制和测试它们之间的关系。 分层皮层在目标2中，我们提出检测氧化脂质，并检验脂质过氧化是 与脑铁、阿尔茨海默病和认知能力下降有关。我们还将研究脂质是否 过氧化物介导AD中与铁相关的认知下降。在目标3中，我们将测定脑铁， （氧化）脂质含量在脑运动区和测试的假设，区域脑铁与 脂质成分与运动功能和下降和运动病理（路易体，血管，AD等）在 老年人。在每一个目标中，我们将研究APOE ε4，阿尔茨海默病的病理学特征， 诊断和性别总的来说，这些研究有可能揭示铁，脂质， (diet和大脑），和APOE ε4增加衰老和AD中的认知和运动下降。这些研究有 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.