Project description:Alzheimer's disease (AD) is an aging-dependent, irreversible neurodegenerative disorder and the most common cause of dementia. The prevailing AD hypothesis points to the central role of altered cleavage of amyloid precursor protein (APP) and formation of toxic amyloid-β (Aβ) deposits in the brain. The lack of efficient AD treatments stems from incomplete knowledge on AD causes and environmental risk factors. The role of lifestyle factors, including diet, in neurological diseases is now beginning to attract considerable attention. One of them is western diet (WD), which can lead to many serious diseases that develop with age. The aim of the study was to investigate whether WD-derived systemic disturbances may accelerate the brain neuroinflammation and amyloidogenesis at the early stages of AD development. To verify this hypothesis, transgenic mice expressing human APP with AD-causing mutations (APPswe) were fed with WD from the 3rd month of age. These mice were compared to APPswe mice, in which short-term high-grade inflammation was induced by injection of lipopolysaccharide (LPS) and to untreated APPswe mice. All experimental subgroups of animals were subsequently analyzed at 4-, 8-, and 12-months of age. APPswe mice at 4- and 8-months-old represent earlier pre-plaque stages of AD, while 12-month-old animals represent later stages of AD, with visible amyloid pathology. Already short time of WD feeding induced in 4-month-old animals such brain neuroinflammation events as enhanced astrogliosis, to a level comparable to that induced by the administration of pro-inflammatory LPS, and microglia activation in 8-month-old mice. Also, WD feeding accelerated increased Aβ production, observed already in 8-month-old animals. These brain changes corresponded to diet-induced metabolic disorders, including increased cholesterol level in 4-months of age, and advanced hypercholesterolemia and fatty liver disease in 8-month-old mice. These results indicate that the westernized pattern of nourishment is an important modifiable risk factor of AD development, and that a healthy, balanced, diet may be one of the most efficient AD prevention methods.

Project description:According to the developmental origins of health and disease (DOHaD) hypothesis, exposure to environmental stressors during early development can cause genetic, epigenetic, or functional changes in tissues that increase disease risk later in life. Atrazine (ATZ) is a commonly used pesticide that frequently contaminates rural and urban water sources at levels above the 3 ppb maximum contaminant level set by the US Environmental Protection Agency. Exposure to ATZ is linked to endocrine disruption, cancer, changes in genome methylation, and alterations in neurochemistry and behavior. This study tests the hypothesis that embryonic exposure to ATZ results in sex-specific changes in behavior, the adult brain transcriptome, and adult body and brain pathology, according to the DOHaD hypothesis. Zebrafish (Danio rerio) embryos were exposed to 0, 0.3, 3, or 30 ppb (ppb; µg/L) ATZ during the period from fertilization through 72 hours post fertilization (hpf), and then were rinsed and raised to maturity with no further exposure. At 9 months post fertilization (mpf), a novel tank test, a light-dark box, and an open field test evaluated adult behavior. Transcriptomic analysis investigated ATZ related differences in gene expression and the brain was evaluated histopathologically for morphometric alterations in the area of the dorsal telencephalon, posterior tuberculum, and raphe populations. At 14 mpf, the body length, weight, and brain weight was measured to evaluate effects of ATZ on mature body and brain size. The 9 mpf adult behavioral tests found non-monotonic, sex-specific behavior changes, with male zebrafish having decreased activity and female zebrafish having increased signs of anxiety. Transcriptomic analysis identified sex-specific alterations, with females having altered expression of genes in pathways related to cancer and organismal injury and males having altered gene expression in organismal development and reproductive system development and function pathways. Morphometric analysis identified a decreased number of cells in male raphe populations and adult zebrafish also had non-monotonic, sex-specific alterations in body length, body weight, and brain weight. This results suggests that developmental exposure to ATZ does cause sex-specific alterations in adult neural function.

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Atrazine Inhalation Causes Neuroinflammation, Apoptosis and Accelerating Brain Aging.

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