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）联系起来， 认知能力下降特发性AD是美国最常见的痴呆症， 病因不明的神经退行性疾病。除了斑块和缠结的积累，AD是 还以脑中氧化还原活性金属铁（Fe）水平显著升高为特征， 脑金属稳态失调假说铁含量升高的基础尚不清楚，但这 补充假设，暴露于铁污染的超细颗粒（UFP） 被认为是AP中反应性最强的成分， 子宫内和出生后终身存在，有助于AD表型。事实上，出生后，这种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; UFP可以 也可以通过嗅觉和三叉神经直接进入大脑，绕过血脑屏障。我们 通过吸入暴露于浓缩环境UFP的小鼠的数据证实了脑Fe的显著升高 以及其他大脑必需金属的变化。像大多数神经退行性疾病一样，AD是 表达的异质性可以反映Fe含量的地理差异 污染.有趣的是，在这方面，美国铁排放量最高的地区与 老年痴呆症死亡率最高。在从出生后早期暴露于 在雄性和雌性小鼠中，已经观察到AD的许多雌性特异性特征： 小胶质细胞活化，与鼻嗅摄取一致，减少了神经元细胞计数的轨迹， 在PND 90时，海马体总淀粉样蛋白和tau蛋白水平升高。巨结肠症， AD的另一个特征是男女都有。这项拟议补充条文的目的，是扩大我们的 目前的研究AP诱导的脑金属污染，其中迄今为止已集中在神经发育 为了检查成年小鼠在治疗后的多个时间点暴露于Fe UFP 6周的影响， exposure.结果指标将包括AD的神经病理学特征，特别是高磷酸化 tau蛋白、β淀粉样蛋白、脑室肥大、髓鞘形成、氧化应激和铁凋亡， 执行功能的措施。这一补充应建立一个模型， AD的机制和与性别有关的脆弱性差异，以及提供重要的数据， 因此，对公众健康的保护。