Neurodevelopmental and neurodegenerative effects of environmental determinants: altering neural cellular populations impacting homeostatic functions and inflammatory response.

环境决定因素的神经发育和神经退行性影响：改变影响稳态功能和炎症反应的神经细胞群。

• 批准号: 10463541
• 负责人: Nicholas Francis Fitz
• 金额: $ 56.63万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463541
• 关键词: ATP binding cassette transporter 1; Acetylation; Adult; Affect; Age; Aging; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease risk; Arsenic; Astrocytes; Biochemical; Bioenergetics; Biogenesis; Blood; Blood - brain barrier anatomy; Brain; Brain Injuries; Brain Pathology; Cell Communication; Cells; Cholesterol; Chronic; Clinical; Cognition; Cognitive deficits; Complement; Complex; Cytoskeleton; DNA; DNA Methylation; Data; Dementia; Development; Disease; Embryonic Development; Environment; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Etiology; Exposure to; Fatty Acids; Functional disorder; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Health; Heavy Metals; Histones; Homeostasis; Human; Image; Immune system; Impaired cognition; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Life; Lipid Peroxidation; Lipids; Liver X Receptor; Lysine; Malignant Neoplasms; Mediating; Membrane; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Microglia; Mitochondria; Modification; Molecular; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Neurophysiology - biologic function; Nuclear Receptors; Organ; Outcome; Oxidative Stress; Oxygen Consumption; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peripheral; Persons; Placenta; Play; Poison; Population; Predisposition; Process; Proteins; RXR; Reactive Oxygen Species; Receptor Signaling; Research; Role; Signal Transduction; Stimulus; Stress; Synapses; Synaptic plasticity; Synaptosomes; Tail; Testing; Toxic Environmental Substances; Toxicant exposure; Transcription Alteration; Untranslated RNA; Water; aging brain; brain cell; cancer cell; cardiovascular disorder risk; cell type; design; disorder risk; epidemiology study; epigenetic marker; epigenetic regulation; epigenome; epigenomics; fatty acid metabolism; gene environment interaction; genetic signature; genome wide association study; histone modification; immune function; improved; in utero; injury and repair; lifestyle factors; lipid transport; metabolic abnormality assessment; mitochondrial dysfunction; nerve injury; neurodevelopment; neuroinflammation; neuron development; neuroprotection; peroxidation; postnatal; prenatal; receptor expression; relating to nervous system; response; response to injury; risk variant; single-cell RNA sequencing; synaptic pruning; transcriptomics; two-photon

Alzheimer’s disease (AD) is the most common form of dementia, influenced by genetic, environmental and lifestyle factors. Environmental factors and gene-environment interactions are poorly understood in AD etiology. Recently the role of glia in Alzheimer’s disease has gained focus, fueled by GWAS discovery of several risk loci in genes related to immune function, and neuronal-glial cell interactions which are essential for synaptic homeostasis and affected in AD. Furthermore, exposure to environmental toxicants such as heavy metals, as well as metalloids, induce epigenetic changes which could alter different neural cell populations accelerating neurodegeneration. To improve our understanding of Alzheimer’s pathogenesis, studies examining how modifiable environmental factors or AD exposome, impact healthy brain aging, glial homeostasis or disease states and neuroinflammation are crucial. Major brain cell types are vulnerable to oxidative stress and both AD and toxicant exposures are associated with mitochondrial dysfunction and elevated lipid peroxidation. In this regard the role of nuclear receptors with firmly established role in neurodevelopment, neuroinflammation and neurodegeneration is particularly important. Activation of RXR/LXR heterodimers induces critical expression of target genes involved in lipid trafficking, efflux (APOE-ABCA1 axis) and synthesis. Perturbation of the LXR- ABCA1-APOE signaling/metabolic axis and dysregulation of cellular metabolism represent an important potential mechanism by which environmental toxicants could further contribute to AD exposome. We hypothesize exogenous environmental factors induce complex pathophysiological interactions between neurons and glial cells through epigenomic and transcriptional changes, altering healthy brain aging, and increasing Alzheimer’s disease risk through changes in bioenergetics and response to inflammatory stimuli. Environmental arsenic (As) is at the top of the list of toxic substances threatening human health (ATSDR 2017 Substance Priority List). Arsenic can easily pass the blood-brain barrier and accumulate in brain. Low-level As in water has been associated with poor global cognition in adults and induced changes in all three epigenetic markers. To test the hypothesis we will determine: 1) epigenetic and transcriptional alterations following As exposure of distinct neural populations (neurons, microglia, astrocytes) during aging; 2) how exposure to As alters glial response to Alzheimer’s disease related neurodegeneration, and 3) changes in synaptic homeostasis, mitochondrial and LXR related lipid trafficking following As exposure. These studies will better define if and how As exposure, as an important part of the AD exposome, could influence healthy brain aging. Furthermore, we will determine how environmental toxicants could alter AD related pathologies including, glia response, neuroinflammation and brain bioenergetics.

阿尔茨海默氏病（AD）是痴呆症的最常见形式，受遗传，环境和生活方式因素的影响。环境因素和基因环境相互作用在AD病因中尚未理解。最近，GLIA在阿尔茨海默氏病中的作用已引起了人们的重点，GWAS在与免疫功能有关的基因中发现了几个风险基因座，以及对突触稳态至关重要的神经元细胞相互作用，并且在AD中受到影响。此外，暴露于环境有毒物质（例如重金属）以及金属遗体会诱导表观遗传变化，这可能会改变不同的神经元细胞群体加速神经变性。为了提高我们对阿尔茨海默氏症发病机理的理解，研究研究了可改变的环境因素或AD暴露，影响健康的脑老化，神经胶质体内稳态或疾病状态以及神经炎症至关重要。主要的脑细胞类型容易受到氧化应激的影响，AD和毒性暴露都与线粒体功能障碍和脂质过氧化升高有关。在这方面，核接收器在神经发育，神经炎症和神经退行性中具有关键作用的作用尤为重要。 RXR/LXR异二聚体的激活诱导参与脂质运输，外排（APOE-ABCA1轴）和合成的靶基因的关键表达。 LXR-ABCA1-APOE信号传导/代谢轴和细胞代谢失调的扰动代表了一种重要的潜在机制，通过该机制，环境有毒物质可以进一步有助于AD暴露。我们假设极端的环境因素通过表观基因组和转录变化诱导神经元和神经胶质细胞之间的复杂病理生理相互作用，改变了健康的大脑衰老，并通过生物能的变化和对炎症刺激的反应来增加阿尔茨海默氏病风险。环境砷（AS）位于威胁人类健康的有毒物质清单中（ATSDR 2017物质优先级清单）。砷可以轻松地通过血脑屏障并在大脑中积聚。低水平的水与成人全球认知不良有关，并诱发了所有三种表观遗传标记的变化。为了检验假设，我们将确定：1）在衰老期间暴露于不同神经吞吐量（神经元，小胶质细胞，星形胶质细胞）之后的表观遗传和转录改变； 2）暴露于随着阿尔茨海默氏病与神经变性相关的神经胶质反应，以及3）突触稳态，线粒体和LXR相关的脂质运输的变化。这些研究将更好地定义是否以及如何作为AD Exposome的重要组成部分，可能会影响健康的大脑衰老。此外，我们将确定环境毒物如何改变与AD相关的病理，包括神经胶质反应，神经炎症和脑生物能学。