Patients with Alzheimer's disease (AD) develop two main pathological changes in the brain: amyloid plaques composed of deposits of abnormally aggregated amyloid ?-protein (A?) and neurofibrillary tangles (NFTs) consisting of abnormal aggregates of hyperphosphorylated tau protein. Amyloid plaques and NFTs are accompanied with chronic inflammation characterized by activated microglia and increased cytokines. Except a small subset of early-onset familial AD cases, 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, insulin resistance and T2DM. Obesity and T2DM are main risk factors of AD, cognitive impairment, vascular dementia, cardiovascular disease, and stroke. Additionally, sustained alterations in blood glucose levels promote vascular inflammation and blood- brain barrier (BBB) impairment. Furthermore, the risk of AD increases with the number of vascular risk factors. According to the vascular hypothesis of AD, dysfunctional BBB play a causal role in the pathogenesis of AD, leading to accumulation of A?, neuroinflammation, neuronal dysfunction, neurodegeneration and, ultimately, dementia of AD. We recently found increased levels of microRNA-34a (miR-34a) in blood exosomes derived from animal models of AD, T2DM and peripheral inflammation. Blood miR-34a levels are elevated in patients with T2DM. We hypothesize that HFD and peripheral inflammation increase miR-34a in blood and increased levels of miR-34a in blood induce brain endothelial cell dysfunction (dysfunctional BBB), leading to an increased risk, early onset and accelerated progression of AD and that miR-34a can be a therapeutic target. This hypothesis will be tested by carrying out the following aims.
In Aim 1, we will produce a miR-34a-deficient AD mouse model and determine the effects of miR-34a deficiency on AD-like pathology and cognitive functions.
In Aim 2, we will prepare extracellular vesicles (EVs) loaded with miR-34a and its inhibitor, intravenously infuse the EVs and determine the effects of EVs loaded with miR-34a and its inhibitor on AD-like pathology and behavioral functions in an AD mouse model. The long-term goals of this project are to determine the role of miR-34a in the pathogenesis of AD and to develop new preventive and therapeutic strategies for AD.
The pathogenesis of late-onset Alzheimer's disease (AD) is unknown and satisfactory treatments for AD are unavailable. We hypothesize that high-fat diet and peripheral inflammation increases a specific microRNA, miR-34a, in blood exosomes and increased miR-34a in blood exosomes causes brain endothelial cell dysfunction, leading to an increased risk, early onset and accelerated progression of AD. In this research project, we will determine the role of blood exosomal miR-34a produced by chromic consumption of high-fat diet in the AD pathogenesis using an animal model of AD.
