Vascular Inflammation and Exosomes as Mediators in Aging and Dementia

衰老的特征在于全身性炎症变化、器官功能障碍和 脆弱衰老与增加的氧化应激和炎症有关，这导致受损的 血管修复、炎症增加和单核细胞粘附增加。这是伴随着 衰老（Sen）内皮细胞（EC）的发展，最初被认为是良性的，但 现在已知是一种持续的炎症输出的来源，称为衰老相关的炎症。 分泌表型（SASP）和其他有害影响，有助于整体下降和脆弱 看到了衰老。血管系统作为一种促进 阿尔茨海默氏症和其他痴呆症，所有这些疾病主要与衰老有关。我们 假设衰老（Sen）内皮细胞（EC）随着衰老而积累， - 促炎环境，其不利地影响血脑屏障（BBB），以及 导致与老年痴呆症有关的神经病理学， 疾病（AD）。为此，我们将使用已建立的，良好表征的人Sen EC体外模型， 研究SASP和来源于Sen EC的外来体对人BBB完整性的影响， 培养的神经元。我们还将分析Sen产生的外泌体的内容物，包括miRNA， vs.早期传代（EP）EC来源于同一供体，并确定是否与Sen共培养 EC、SASP或exosomes增加不同神经细胞对Aβ42毒性的易感性 缩氨酸最后，我们将研究是否外源性施用来源于Sen的外来体， EC损害BBB完整性并促进男性和女性体内AD相关神经病理学 TgF 344-AD大鼠，其是早发性阿尔茨海默病模型。年龄和性别匹配的同源野生型 将大鼠用作对照。血脑屏障完整性，神经炎症，神经元连接，神经细胞学 缠结和淀粉样蛋白斑块将使用最先进的成像模式进行研究， 生化和细胞分析。这项工作有可能确定新的机制， 痴呆症的发展，如阿尔茨海默氏症，这是接近流行病的比例，在我们的 人口老龄化这些发现有可能导致新的治疗靶点。

Aging is characterized by the development of systemic inflammatory changes, organ dysfunction and frailty. Aging is associated with increased oxidative stress and inflammation, which leads to impaired vascular repair, increased inflammation and increased monocyte adhesion. This is accompanied by the development of senescent (Sen) endothelial cells (EC), which originally were thought to be benign, but are now known to be a source of a sustained inflammatory output known as the senescence associated secretory phenotype (SASP) and other deleterious effects that contribute to the overall decline and frailty seen with aging. The vasculature has been under investigated as a contributor to the development of Alzheimer’s and other dementias, all of which are diseases predominantly associated with aging. We hypothesize that senescent (Sen) endothelial cells (ECs), which accumulate with aging, create a pro-inflammatory environment that adversely affects the blood brain barrier (BBB) and contributes to neuropathology implicated in age-associated dementias such as Alzheimer’s disease (AD). To this end we will use an established, well-characterized in vitro model of human Sen EC to study the effects of the SASP and exosomes derived from Sen EC, on human BBB integrity and neurons in culture. We will also analyze the content, including miRNA, of exosomes produced by Sen vs. early passage (EP) EC derived from the same donor, and determine whether co-culture with Sen ECs, SASP or exosomes increases the susceptibility of different neural cells to the toxicity of Aβ42 peptides. Lastly, we will investigate whether exogenous administration of exosomes derived from Sen EC compromises BBB integrity and promotes AD-relevant neuropathology in vivo in male and female TgF344-AD rats, which are an early onset Alzheimer's model. Age- and sex-matched congenic wild type rats will be used as controls. BBB integrity, neuroinflammation, neuronal connectivity, neurofibrillary tangles and amyloid plaques will be studied using state of the art imaging modalities as well as biochemical and cellular analysis. This work has the potential to identify new mechanisms contributing to the development of dementias, such as Alzheimer’s, which is approaching epidemic proportions in our aging population. Such findings have the potential to lead to new therapeutic targets.