Role of extracellular vesicles in the high-fat diet-induced risk of Alzheimer disease

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Project summary/Abstract Amyloid plaques composed of deposits of abnormally aggregated amyloid β-protein and neurofibrillary tangles (NFTs) consisting of abnormal aggregates of hyperphosphorylated tau protein in the brain are two main pathological changes in patients with Alzheimer's disease (AD). Amyloid plaques and NFTs are accompanied with chronic inflammation characterized by activated microglia and increased cytokines. The causes for the vast majority of AD cases are unknown and satisfactory therapeutic and preventive measures for AD are unavailable. Therefore, an urgent need exists to identify the molecular mechanisms that increase the risk for the vast majority of AD cases and for development of preventive and therapeutic measures. Over 30% of adults are currently classified as obese in the US and obesity is considered to be responsible for up to 70-90% of type 2 diabetes mellitus (T2DM) cases. Consumption of high fat diets (HFD) is strongly associated with obesity and T2DM. Obesity and T2DM are linked to decreases in cognitive functions in older adults and strong risk factors of AD. Furthermore, AD patients show decreases in glucose uptake and insulin sensitivity in the brain and have increased risk for developing T2DM. Additionally, obesity and T2DM are main vascular risk factors and produce a number of macro- and micro-vascular complications including blood-brain barrier (BBB) dysfunction and inflammation. According to the vascular hypothesis of AD, vascular risk factors including diabetes, obesity and systemic inflammation induce hypoperfusion, hypoxia and BBB dysfunction, which cause reduced Aβ clearance across the BBB, accumulation of brain Aβ, and NFT formation, leading to neurodegeneration and, ultimately, AD dementia. We hypothesize that blood extracellular vesicles (EVs) associated with obesity and T2DM have the characteristics of RNA and/or protein profiles that induce the BBB dysfunction, brain glucose hypometabolism and neuroinflammation in the brain, leading to an increased risk and accelerated progression of AD. RNAs and proteins abundantly found in EVs have important roles in cell- to-cell communication and are involved in immune regulation, inflammatory responses, cell metabolism, metabolic syndrome and neurological disorders. In order to test the hypothesis, we will isolate blood EVs from HFD- and normal chow diet (NCD)-fed mice, intravenously infuse the EVs into AD model mice and determine body weight, glucose metabolism, BBB changes, AD-like and inflammatory pathology and behavioral functions (Aim 1). We will determine protein and RNA profiles of blood EVs from AD model, HFD- and NCD-fed mice and perform their signaling pathway analysis (Aim 2). The immediate goal of this study is to determine the role of blood EVs produced by chronic consumption of HFD in the AD pathogenesis. If proven true, this project will open new research avenues to identify specific molecules (microRNAs and/or proteins) in EVs, which are responsible for the increased risk of AD in obese and T2DM patients and to ultimately prevent and treat AD.