Air Pollution, Elevated Brain Iron and Alzheimer's Disease

空气污染、脑铁含量升高和阿尔茨海默病

• 批准号: 10285494
• 负责人: Deborah A Cory-Slechta
• 金额: $ 38.08万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10285494
• 关键词: Adult; Affect; Aging; Air Pollution; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Amygdaloid structure; Amyloid; Amyloid beta-Protein; Amyloid deposition; Area; Behavioral; Biological; Biological Models; Birth; Blood; Blood - brain barrier anatomy; Brain; Brain region; Bypass; Cell Count; Cerebrum; Cognitive; Copper; DNA Sequence Alteration; Data; Dementia; Disease; Environmental Risk Factor; Epidemiology; Etiology; Exposure to; Female; Funding; Geography; Grant; Health protection; Hippocampus (Brain); Histologic; Homeostasis; Human; Impaired cognition; Impairment; Inductively Coupled Plasma Mass Spectrometry; Inflammation; Inhalation; Inhalation Exposure; Iron; Lead levels; Link; Maps; Mediating; Memory; Meta-Analysis; Metals; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurofibrillary Tangles; Neurons; Nose; Nucleus Accumbens; Olfactory Nerve; Olfactory dysfunction; Olfactory tract; Outcome Measure; Oxidation-Reduction; Oxidative Stress; Particulate Matter; Pathologic; Pathway interactions; Peripheral; Public Health; Regulation; Reporting; Risk Factors; Role; Schizophrenia; Senile Plaques; Sensorimotor functions; Sex Differences; Site; Stream; Suggestion; Synapses; Third Pregnancy Trimester; Time; Trigeminal nerve structure; abeta accumulation; air contaminant; air filter; behavior measurement; behavior test; disease phenotype; economic cost; epidemiology study; executive function; experimental study; fetal; geographic difference; high efficiency particulate air filter; in utero; macrophage; male; mortality; myelination; nanoparticle; nanoparticle exposure; neural network; neurodegenerative dementia; olfactory bulb; piriform cortex; postnatal; postnatal period; pre-clinical; sex; social; tau Proteins; ultrafine particle; uptake; virtual; young adult

ABSTRACT Numerous epidemiological studies have now linked air pollution (AP) with Alzheimer’s Disease (AD) and cognitive decline. Idiopathic AD, the most common form of dementia in the US, is a female-biased neurodegenerative disease of unknown etiology. In addition to the accumulation of plaques and tangles, AD is also characterized by marked elevations in brain levels of the redox active metal, iron (Fe), giving rise to a brain metal dyshomeostasis hypothesis for AD. The basis for the elevated Fe is not clear, but this supplement hypothesizes that exposures to Fe contamination from the ultrafine particle (UFP) component of AP, considered the most reactive component of AP, to which exposures can begin in utero and be lifelong following birth, contributes to the AD phenotype. Indeed, post-birth, such UFPs and associated contaminants move directly into blood stream, bypassing macrophages to each brain; UFPs can also be directly taken up into brain via olfactory and trigeminal nerves, bypassing the blood brain barrier. Our data from mice exposed via inhalation to concentrated ambient UFPs confirms significant elevation of brain Fe and alterations in other essential brain metals as well. Like most neurodegenerative diseases, AD is heterogeneous in expression which could reflect the geographical differences in the extent of Fe contamination. Interestingly, in that regard, the levels of highest Fe emissions in the U.S. overlap with areas of highest Alzheimer’s disease mortality. In preliminary data obtained from early postnatal exposures of both male and female mice, numerous female-specific features of AD have been seen: increased olfactory bulb microglial activation, consistent with nasal olfactory uptake, decreased trajectory of neuronal cell counts in nucleus accumbens, and increased levels of total hippocampal amyloids and tau at PND90. Ventriculomegaly, another feature seen in AD, was found in both sexes. The aim of this proposed supplement is to extend our current studies of AP-induced brain metal contamination, which to date has focused on neurodevelopmental disorders, to examine the effects of a 6 week exposure of adult mice to Fe UFPs at multiple time-points post exposure. Outcome measures will include neuropathological features of AD, specifically hyperphosphyorylated tau, beta amyloids, ventriculomegaly, myelination, and oxidative stress and ferroptosis, with behavioral measures of executive function. This supplement should establish a model that could be critical to defining mechanisms of AD and sex-related differences in vulnerability, as well as to provide data that is important to regulation of AP, and consequently to public health protection.

抽象的 现在，许多流行病学研究已将空气污染（AP）与阿尔茨海默氏病（AD）和 认知能力下降。特发性广告是美国最常见的痴呆症形式，是女性偏见 未知病因的神经退行性疾病。除了斑块和缠结的积累外，AD是 还以氧化还原活性金属（Fe）的大脑水平明显升高的特征，导致 AD的脑金属dyshomeostasis假设。升高的铁的基础尚不清楚，但是 补充假设暴露于超铁颗粒（UFP）的Fe污染 AP的组成部分，被认为是AP的最具反应性分量，可以从中开始 子宫出生后的终生，有助于AD表型。确实，出生后，这样的UFP和 相关的污染物直接进入血液，绕过每个大脑巨噬细胞。 UFP可以 也可以通过嗅觉和三叉神经直接吸收大脑，绕过血脑屏障。我们的 通过吸入暴露于浓缩环境UFP的小鼠的数据证实了脑力的显着升高 以及其他必要的大脑金属的改变。像大多数神经退行性疾病一样，AD是 表达异质，这可能反映了Fe程度的地理差异 污染。有趣的是，在这方面，美国最高的FE排放水平与 阿尔茨海默氏病死亡率最高。在从两者的早期暴露中获得的初步数据中 雄性和雌性小鼠，已经看到了许多女性特异性特征：嗅球增加 小胶质细胞激活与鼻嗅觉摄取一致，降低了神经元细胞计数的轨迹 伏隔核，以及在PND90处的海马淀粉样蛋白和TAU的水平升高。心室肿瘤， 在AD中看到的另一个功能是在两个性别中发现的。该提议的补充的目的是扩展我们 当前对AP诱导的脑金属污染的研究，迄今为止，该污染的重点是神经发育 疾病，检查成年小鼠在多个时间点的6周暴露于Fe UFP的影响 接触。结果指标将包括AD的神经病理特征，特别是高磷酸化的 tau，β-淀粉样蛋白，室性肿瘤，髓鞘形成和氧化应激和铁毒性，行为 执行功能的度量。该补充应建立一个可能对定义至关重要的模型 AD的机制和与性别相关的脆弱性差异，以及提供对数据至关重要的数据 AP的监管，因此对公共卫生保护。