Dissecting the Role of Arachidonic Acid Metabolic Pathways Involved in Resolution Versus Progression of PM-Induced Cardiometabolic Toxicity

项目摘要/摘要（广告行政副刊）

PROJECT SUMMARY/ABSTRACT (AD-focused Administrative Supplement) The estimated number of people with dementia is predicted to triple by 2050 worldwide. Together with the lack of effective treatments to stop, slow or prevent Alzheimer's disease (AD) and its related dementias, the best strategy to limit the predicted incidence is to mitigate AD risk factors. Exposure to ambient particulate matter (PM) is emerging as a modifiable environmental risk factor for AD. However, the mechanism by which PM exposure contributes to the development of AD is not known. Our previous research has shown that exposures to ultrafine particles (UFP) and diesel exhaust (DE) in mice lead to chronic inflammation, increased lipid peroxidation in lung and systemic tissues, disturbances in lipid metabolism and plasma lipoproteins, and the development of liver steatosis and atherosclerosis, all components of the commonly called cardiometabolic syndrome. Recent studies suggest that cardiovascular and metabolic disorders may play a critical role in the development of AD. In fact, AD and cardiometabolic syndrome share major risk factors, in addition to cerebrovascular and cardiovascular changes occurring years before symptoms occur. Based on additional research from our laboratories, both UFP and DE exposures in mice trigger astrocyte and microglia activation which lead to neuroinflammation and/or cause neurotoxicity affecting neurons in the brain and accelerating cognitive decline. We will augment the Parental R01 (ES033703, RESTORE RFA) by extending its focus on hepatic steatosis and atherosclerosis with the analyses of brain tissue in the same hyperlipidemic mouse model (low-density lipoprotein knockout, Ldlr KO), placed on a high fat diet (HFD). Importantly, Ldlr deficiency and HFD administration have been associated with worsened AD-related phenotypes and cognitive dysfunction in a transgenic mouse model of AD through impairment of antioxidant system defenses leading to oxidative stress and neuronal apoptosis. Therefore, while this is not a typical mouse model for the study of AD, we do expect significant neuroinflammatory and neurodegenerative effects. Our overall objective is to identify critical pathways in the Lung-Heart-Brain Axis that could be involved in the development of chronic inflammation in the brain. Our hypothesis for this AD-focused Research Supplement is that PM exposure promotes proinflammatory and degenerative effects in the brain via activation of the 5-Lipoxygenase pathway, overpowering the counteracting actions of homeostatic protective responses when that activation is persistent. Our hypothesis will be tested via the following aims: Supplemental Specific Aim 1) Determine molecular pathways involved in the development and progression of neuroinflammation and AD-relevant changes in the brain after exposure to UFP; and Supplemental Specific Aim 2) Dissect molecular pathways involved in the development and progression of neuroinflammation and AD-relevant changes in the brain after exposure to DE. Results from this Supplement could provide convincing preliminary data for additional proposals to investigate environmental factors that may induce AD and other potential drivers of cognitive decline.