SUMMARY: Air pollution exposure has well-appreciated negative impacts on cardiovascular, pulmonary and neurological systems, including numerous epidemiological and toxicological reports documenting increased risk for Alzheimer’s Disease (AD). During pregnancy, unique molecular adaptations of the cerebral endothelium occur to counteract the effects of circulating vasoactive factors and preserve BBB properties and brain homeostasis. While these adaptations appear to maintain brain homeostasis during gestation, vulnerability to neuroinflammatory responses to inhaled toxicant-induced circulatory factors are unstudied. Importantly, hypertensive disorders of pregnancy represent a major risk factor for the development of AD in later life – and air pollution exposure can promote gestational hypertensive scenarios. Inhaled ozone (O3) induces proteolytic activity in the lung, leading to shredding of protein fragments into the circulation that are bioreactive, promoting cerebrovascular endothelial inflammatory reactions. Our prior reports demonstrated that acute air pollutant exposure thusly impairs blood-brain barrier and activates central nervous system (CNS) glia (microglia and astrocytes) in brain regions, including the cortex, limbic structures and in the cerebellum, regions essential for learning, memory and cognition. Neurodegenerative sequelae such as pathological β- amyloid accumulation was observed following an acute exposure of O3 in rodents with advanced age. Neuroinflammation plays a pivotal role in the pathobiology of AD. β-amyloid accumulation and pathological tau protein phosphorylation leading to formation of neurofibrillary tangles (referred as taupathy) are hallmarks of AD pathology leading to dementia, deficits in cognitive and memory function, all of which are potentiated by neuroinflammation. Neuroinflammatory events from air pollutant exposure, compounded by hypertensive conditions during gestation, may dispose women to greater risk of AD-associated pathology in later-life. In the parent R01, we have identified O3-induced cardiovascular and placental dysfunctional sequelae similar to preeclampsia. We wish to now examine the long-term consequences of pollution-induced neuroinflammation in the maternal brain in the context of taupathy and AD. We hypothesize that the combined neuroinflammatory and gestational hypertensive consequences of gestational air pollution exposure augment risk taupathy in later-life. To test this, we will first assess the extent to which gestational exposure to O3 exacerbates acute neuroinflammatory effects compared non-pregnant mouse exposures. Secondly, we will determine whether O3 exposure-induced neuroinflammation during pregnancy accelerates the onset of taupathy and exacerbates the magnitude of taupathy and neuroinflammation. Using wildtype and Tau P301S transgenic mice (mutant human microtubule-associated protein tau), we will examine the long-term effects of O3 exposure on the onset of taupathy and magnit...