Neuropathologic-Epidemiological Study of Metallomics and Alzheimer's Disease

主要研究者/项目负责人（最后，第一，中间）：Morris，Martha克莱尔 这个R 01申请，题为“金属组学和阿尔茨海默氏症的流行病学神经病理学研究 疾病”是一个新的提交，以回应PAR-15-356。预计到2050年， 将有1350万美国人患有AD，成本为1.1万亿美元。近期药物大规模III期临床试验 靶向已知的参与AD的途径要么未能使患者受益，要么表明非常有限， 功效虽然β淀粉样蛋白（Aβ）可能是该疾病的主要驱动因素，但多项失败的临床试验表明， 靶向该肽的药物提示Aβ是AD的不良治疗靶点。铁积累在 影响AD的大脑区域，并有可能通过引起氧化应激来推动疾病进展 以及Aβ和tau的聚集，因此是替代的治疗靶点。在之前的研究中，我们发现 脑的铁负荷（反映在CSF铁蛋白水平）对多个纵向 AD的结局与疾病中更确定的因素（tau和Aβ）在程度上相当。我们有 初步数据显示，脑铁水平与神经系统缠结之间存在强烈的正相关性， 病理学，特别是APOE-ε4携带者。没有一个系统的，有力的，详细的 探索AD患者的脑铁水平。在这里，我们建议使用一个大的，良好的特点死后队列 一项名为“拉什记忆和衰老项目”的研究，调查了680名尸检的AD患者的脑铁浓度。 大脑使用先进的技术。我们将研究脑铁负荷对AD的影响 神经病理学和认知临床史;研究AD中铁蓄积的潜在原因，包括 饮食和遗传因素;并利用先进的蛋白质组学探索铁升高的神经化学机制 和金属蛋白质组学。这项基础研究有可能（1）确定铁浓度是否 与疾病相关，（2）验证铁作为AD的治疗靶点，（3）发现新的分子靶点 （4）确定饮食是否影响脑铁水平和AD风险，以及（6）确定是否 遗传因素，包括APOE等位基因变异，对AD患者铁的影响。 PHS 398/2590（2004年9月修订，2006年4月重新印发）

Principal Investigator/Program Director (Last, First, Middle): Morris, Martha Clare This R01 application, entitled “Epidemiological Neuropathologic Study of Metallomics and Alzheimer's Disease” is a new submission in response to PAR-15-356. By the year 2050 it is projected that there will be 13.5 million Americans with AD at a cost of $1.1 trillion. Recent large-scale phase III clinical trials of drugs targeting known pathways involved in AD have either failed to benefit patients, or indicated very limited efficacy. Whereas beta amyloid (Aβ) may be a principal driver of the disease, multiple failed clinical trials of drugs targeting this peptide suggest that Aβ is a poor therapeutic target for AD. Iron accumulates in the affected brain regions in AD, and has the potential to drive disease progression by causing oxidative stress and the aggregation of Aβ and tau, and is thus an alternate therapeutic target. In previous studies we showed that the iron burden of the brain (as reflected in CSF ferritin levels) has an effect on multiple longitudinal outcomes of AD comparable in magnitude to more established factors in the disease: tau and Aβ. We have preliminary data showing a strong positive association between brain iron levels and neurofibrillary tangle pathology, particularly in APOE-ε4 carriers. There has not been a systematic, well powered, and detailed exploration of brain iron levels in AD. Here, we propose to use a large, well-characterized post mortem cohort study, the Rush Memory and Aging Project, to investigate brain iron concentrations in AD of 680 autopsied brains using advanced techniques. We will investigate the impact of the iron load of the brain on AD neuropathology and cognitive clinical history; investigate potential causes of iron accumulation in AD including diet, and genetic factors; and explore neurochemical mechanisms of iron elevation using advanced proteomics and metalloproteomics. This foundational study has the potential to (1) establish whether iron concentrations are related to the disease, (2) validate iron as a therapeutic target for AD, (3) discover new molecular targets for lowering iron, (4) identify whether diet influences brain iron levels and AD risk, and (6) determine whether genetic factors, including APOE allele variation, impacts on iron in AD. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page