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

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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.