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

阿尔茨海默病（AD）是最常见的痴呆症，受遗传、环境和生活方式因素的影响。在阿尔茨海默病的病因学中，环境因素和基因-环境相互作用知之甚少。最近，神经胶质细胞在阿尔茨海默病中的作用得到了关注，这是因为GWAS发现了与免疫功能相关的基因中的几个风险位点，以及神经元-神经胶质细胞相互作用，这些基因对突触稳态至关重要，并影响阿尔茨海默病。此外，暴露于环境有毒物质，如重金属，以及类金属，诱导表观遗传变化，可能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暴露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是至关重要的。主要的脑细胞类型易受氧化应激的影响，AD和毒物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，核受体在神经发育、神经炎症和神经退行性变中的作用尤为重要。RXR/LXR异源二聚体的激活诱导了参与脂质运输、外排（APOE-ABCA1轴）和合成的关键靶基因的表达。LXR- ABCA1-APOE信号/代谢轴的扰动和细胞代谢的失调是环境毒物进一步促进AD暴露的重要潜在机制。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相互作用，改变健康的大脑衰老，并通过改变生物能量学和对炎症刺激的反应增加阿尔茨海默病的风险。环境砷（As）在威胁人类健康的有毒物质清单（ATSDR 2017物质优先清单）中名列榜首。砷很容易通过血脑屏障，在大脑中积累。水中低水平的砷与成人全球认知能力低下有关，并引起所有三种表观遗传标记的变化。为了验证这一假设，我们将确定：1)衰老过程中不同神经群（神经元、小胶质细胞、星形胶质细胞）暴露于砷后的表观遗传和转录变化；2)暴露于砷如何改变神经胶质对阿尔茨海默病相关神经变性的反应，以及3)暴露于砷后突触稳态、线粒体和LXR相关脂质运输的变化。这些研究将更好地确定As暴露作为AD暴露的重要组成部分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，神经炎症和脑生物能量学。

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.