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: 10612071
• 负责人: Nicholas Francis Fitz
• 金额: $ 55.19万
• 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/10612071
• 关键词: ADD-1 protein; ATP binding cassette transporter 1; Acceleration; 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; Central Nervous System; Child; Cholesterol; Chronic; Clinical; Cognition; Cognitive deficits; Complement; Complex; Cytoskeletal Proteins; 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; Methylation; Microglia; Mitochondria; Modification; Molecular; Nerve Degeneration; 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; 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 injury; 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; mitochondrial dysfunction; nerve injury; neural; neurodevelopment; neuroinflammation; neuron development; neuroprotection; peroxidation; postnatal; prenatal; receptor expression; 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病因学中知之甚少。最近，神经胶质在阿尔茨海默病中的作用得到了关注，GWAS发现了与免疫功能相关的基因中的几个风险位点，以及对突触稳态至关重要并在AD中受影响的神经元-神经胶质细胞相互作用。此外，暴露于环境毒物，如重金属，以及类金属，诱导表观遗传变化，这可能会改变不同的神经细胞群加速神经变性。为了提高我们对阿尔茨海默病发病机制的理解，研究可改变的环境因素或AD紊乱如何影响健康的大脑衰老，神经胶质稳态或疾病状态和神经炎症至关重要。主要脑细胞类型易受氧化应激的影响，AD和毒物暴露均与线粒体功能障碍和脂质过氧化升高相关。在这方面，在神经发育、神经炎症和神经变性中具有牢固确立的作用的核受体的作用特别重要。RXR/LXR异二聚体的激活诱导参与脂质转运、外排（APOE-ABCA 1轴）和合成的靶基因的关键表达。LXR-ABCA 1-APOE信号传导/代谢轴的扰动和细胞代谢的失调代表了环境毒物可能进一步导致AD紊乱的重要潜在机制。我们假设外源性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复杂的病理生理学相互作用，改变健康的大脑衰老，并通过生物能量学变化和对炎症刺激的反应增加阿尔茨海默病的风险。环境砷（As）是威胁人类健康的有毒物质列表（ATSDR 2017年物质优先列表）的顶部。砷可通过血脑屏障在脑内蓄积。水中低水平的砷与成年人的全球认知能力差有关，并引起所有三个表观遗传标记的变化。为了验证这一假设，我们将确定：1）在老化期间不同神经群体（神经元、小胶质细胞、星形胶质细胞）暴露于As后的表观遗传和转录改变; 2）暴露于As如何改变胶质细胞对阿尔茨海默病相关神经变性的反应，以及3）暴露于As后突触稳态、线粒体和LXR相关脂质运输的变化。这些研究将更好地定义作为AD疾病组的重要组成部分，As暴露是否以及如何影响健康的大脑衰老。此外，我们将确定环境毒物如何改变AD相关病理，包括神经胶质反应、神经炎症和大脑生物能量学。