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.

摘要 许多流行病学研究现已将空气污染(AP)与阿尔茨海默病(AD)和 认知能力下降。特发性阿尔茨海默病是美国最常见的痴呆症，是一种偏向女性的疾病 病因不明的神经退行性疾病。除了斑块和缠结的堆积，AD是 同样的特点是大脑中氧化还原活性金属铁(Fe)的水平显著升高，导致 阿尔茨海默病的脑金属代谢紊乱假说。铁升高的基础尚不清楚，但这一点 补充假设暴露于超细颗粒(UFP)的铁污染 AP的成分，被认为是AP中反应最活跃的成分，暴露于AP可从 子宫和出生后终生，有助于AD表型。事实上，出生后，这样的UFP和 相关污染物直接进入血流，绕过巨噬细胞进入每个大脑；超低密度脂蛋白可以 也可通过嗅觉和三叉神经直接进入大脑，绕过血脑屏障。我们的 吸入高浓度环境UFP的小鼠的数据证实脑铁显著升高 以及其他大脑必需金属元素的变化。像大多数神经退行性疾病一样，阿尔茨海默病 表达的异质性，可以反映铁的程度的地理差异 污染。有趣的是，在这方面，美国最高的铁排放水平与 阿尔茨海默病死亡率最高。在从出生后早期接触这两种动物获得的初步数据中 雄性和雌性小鼠，许多雌性特有的阿尔茨海默病特征已经被看到：嗅球增加 小胶质细胞激活，与鼻嗅觉摄取一致，神经细胞计数减少的轨迹 伏隔核，并在PND90时增加海马总淀粉样蛋白和tau的水平。脑室扩大， 在AD中看到的另一个特征，在两性中都发现了。这项拟议的附录的目的是扩大我们的 目前对AP引起的脑金属污染的研究，目前主要集中在神经发育方面 为了检测成年小鼠在多个时间点暴露于铁超氧化物歧化酶6周后的影响 曝光。结果指标将包括阿尔茨海默病的神经病理特征，特别是过度磷酸化 Tau、β淀粉样蛋白、脑室增大、髓鞘形成、氧化应激和铁性下垂，并伴有行为 执行职能的衡量标准。这一补充应该建立一个模型，该模型可能对定义 AD的机制和性别相关的脆弱性差异，以及提供对以下方面重要的数据 对急性呼吸道合并症的监管，以及由此对公共卫生的保护。