Role of diet-induced miR-34a in Alzheimer disease and dementia

项目摘要/摘要 阿尔茨海默病(AD)患者大脑出现两种主要病变：淀粉样斑块 由异常聚集的淀粉样蛋白β蛋白(Aβ)和神经原纤维缠结(NFT)沉积组成 由过度磷酸化的tau蛋白的异常聚集组成。淀粉样斑块和NFT是 伴有慢性炎症，以小胶质细胞激活和细胞因子增加为特征。除 在少数早发性家族性AD病例中，绝大多数AD病例的病因尚不清楚， 目前尚无令人满意的AD治疗和预防措施。因此，迫切需要 确定增加绝大多数AD病例和发病风险的分子机制 预防和治疗措施。在美国，超过30%的成年人目前被归类为肥胖 肥胖被认为是高达70%-90%的2型糖尿病(T2 DM)病例的原因。 高脂饮食(HFD)的摄入与肥胖、胰岛素抵抗和T2 DM密切相关。肥胖 和T2 DM是AD、认知障碍、血管性痴呆、心血管疾病的主要危险因素 卒中。此外，血糖水平的持续变化会促进血管炎症和血液- 脑屏障(BBB)损害。此外，AD的风险随着血管危险因素的增加而增加。 根据AD的血管假说，血脑屏障功能障碍在AD的发病机制中起着因果作用。 导致Aβ积聚，神经炎症，神经元功能障碍，神经变性，最终， 阿尔茨海默病。我们最近发现血液外切体中microRNA-34a(miR-34a)的水平增加 来自AD、T2 DM和外周炎症的动物模型。患者血液miR-34a水平升高 合并T2 DM。我们假设HFD和外周炎症增加了血液中miR-34a并增加了 血液中miR-34a的水平导致脑内皮细胞功能障碍(BBB)，导致 我们认为，miR-34a可以作为治疗的靶点，从而增加AD的风险、提早发病和加速进展。 这一假设将通过实现以下目标来检验。在目标1中，我们将产生缺乏miR-34a的 建立AD小鼠模型，确定miR-34a缺乏对AD样病理和认知功能的影响。 在目标2中，我们将制备负载miR-34a及其抑制剂的细胞外小泡(Ev)，静脉输注 并检测携带miR-34a及其抑制剂的EVS对AD样病理和 AD小鼠模型的行为功能。该项目的长期目标是确定 目的：探讨MIR-34a在阿尔茨海默病发病机制中的作用，并探索防治阿尔茨海默病的新策略。

Project Summary / Abstract Patients with Alzheimer's disease (AD) develop two main pathological changes in the brain: amyloid plaques composed of deposits of abnormally aggregated amyloid β-protein (Aβ) 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 Aβ, 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.