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) 是最常见的痴呆症，受遗传、环境和生活方式因素的影响。最近，人们对阿尔茨海默氏病的神经胶质细胞的作用了解甚少。 GWAS 发现了与免疫功能和神经元-胶质细胞相互作用相关的基因中的几个风险位点，这些位点对于突触稳态至关重要，并且在 AD 中受到影响。类金属诱导的表观遗传变化可能会改变不同的神经细胞群，从而加速神经变性，为了提高我们对阿尔茨海默氏症发病机制的了解，研究可改变的环境因素或 AD 暴露体如何影响健康的大脑衰老、神经胶质稳态或疾病状态以及神经炎症至关重要。细胞类型容易受到氧化应激的影响，AD 和有毒物质暴露均与线粒体功能障碍和脂质过氧化升高有关。 RXR/LXR 异源二聚体的激活会诱导参与脂质运输、流出（APOE-ABCA1 轴）和 LXR-ABCA1-APOE 信号/代谢轴的扰动和失调的靶基因的关键表达。细胞代谢的变化代表了环境毒物可以进一步促进 AD 暴露的重要潜在机制，我们认为外源环境因素会诱导 AD 之间复杂的病理生理相互作用。通过表观基因组和转录变化影响神经元和神经胶质细胞，改变健康的大脑老化，并通过改变生物能量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 (ATSDR) 中的首位。 ) 2017 年优先物质清单）。水中的低浓度砷与成年人的整体认知能力较差有关，并会引起这三种疾病的变化。为了检验这一假设，我们将确定：1）不同神经群体（神经元、小胶质细胞、星形胶质细胞）在衰老过程中暴露于 As 后的表观遗传和转录变化；2）暴露于 As 会如何改变神经胶质细胞对阿尔茨海默病相关神经变性的反应，以及3）砷暴露后突触稳态、线粒体和 LXR 相关脂质运输的变化这些研究将更好地确定砷暴露作为 AD 暴露组的重要组成部分是否以及如何影响健康。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学。