Discovering Novel Mechanisms and Treatment for Aging-Related Dementia: Probing Medin and Abeta Vasculopathy

摘要 血管性痴呆(Vad)是导致痴呆症的第二大常见原因，也是最常见的。 患者年龄74岁。在老龄化的退伍军人群体中，痴呆症是一个严重的卫生保健问题，它影响着 7.3%的退伍军人≥为65岁1。为了预防或治疗VaD，了解其早期的病理生理机制是至关重要的。 特别是学习血管疾病和炎症，这一过程发生在VAD之前几十年， 调节神经炎症和神经退行性变。我们已经确定并描述了一种新的推定 血管衰老剂，麦迪，人类最常见的淀粉样蛋白之一，发现数量更多 在血管性痴呆和阿尔茨海默病(AD)患者中，可导致内皮功能障碍、促炎 类似心血管危险因子(CVRF)的激活，以及加剧对内皮细胞的缺氧性损伤 (ECS)。在血管疾病的后期，动脉粥样硬化和血栓栓塞性改变可导致缺血。 以及脑组织缺氧或中风，这是导致死亡的第五大原因。调查因素，如梅因， 可能会加剧这种伤害，这将导致新的治疗目标。此外，我们还展示了 含单唾液酸神经节苷脂的纳米脂质体(NLGM1，磷脂颗粒&100 nm)可保护小鼠 缺氧和氧化应激导致的内皮功能障碍和血管炎症。基于这些初始的 我们的总体目标是研究衰老的血管系统如何影响神经炎症和 功能，并确定新的治疗目标和干预措施，以减轻VaD的缺氧性损伤。在目标1中，我们将 建立脑血管炎症调节神经炎症和 神经退行性变。在这里，我们将使用2D细胞，新型3D血管脑器官芯片和分离的体外 来自VAD、AD或认知正常的脑供者的侧支脑动脉以确定血管 Medin或CVRF诱导的炎症调节星形胶质细胞和小胶质细胞炎症并影响神经元 功能和生存能力。在目标2中，我们将确定Medin在调节缺氧性神经血管单位中的作用。 受伤。我们还将测试NLGM1是否可以保护脑细胞成分免受缺氧性损伤 使用3D芯片模型的神经血管单元并进行初步研究，以测试NLGM1是否可以保护 抗小鼠大脑中动脉阻塞所致缺氧性损伤。使用新的细胞和人体组织模型 由我们团队开发的这项建议可能会影响我们对VaD早期起源的基本理解， 确定并表征Medin作为一种新的治疗靶点，并验证NLGM1作为一种新的治疗选择。

Abstract Vascular dementia (VaD) is the second most common cause of dementia overall and the most common in patients < 74 years old. In an aging veteran population, dementia is a critical health care issue that affects 7.3% of veterans ≥ 65 years old1. To prevent or manage VaD, it is critical to understand its early pathophysiology, specifically learning how vascular disease and inflammation, a process that occurs decades before VaD, modulate neuroinflammation and neurodegeneration. We have identified and characterized a novel putative agent for vascular aging, medin, one of the most common human amyloid proteins, found in greater quantities in VaD and Alzheimer's disease (AD) patients, and which can cause endothelial dysfunction, pro-inflammatory activation similar to cardiovascular risk factors (CVRFs), as well as exacerbate hypoxic injury to endothelial cells (ECs). In later stages of vascular disease, atherosclerotic and thromboembolic changes can lead to ischemia and brain tissue hypoxia or stroke, the 5th major cause of mortality. Investigating factors, such as medin, that could potentially exacerbate this injury would lead to new treatment targets. Additionally, we showed that monosialoganglioside-containing nanoliposomes (NLGM1, phospholipid particles <100 nm) protect against hypoxia and oxidative stress-induced endothelial dysfunction and vascular inflammation. Based on these initial discoveries, our overall goal is to investigate how the aging vasculature influences neural inflammation and function and identify novel treatment targets and intervention to mitigate hypoxic injury in VaD. In Aim 1 we will establish mechanisms by which cerebrovascular inflammation modulates neuroinflammation and neurodegeneration. Here we will use 2D cell, novel 3D vascularized brain organ-on-a-chip and isolated ex-vivo collateral cerebral arteries from brain donors with VaD, AD or normal cognition to determine how vascular inflammation induced by medin or CVRFs modulate astrocyte and microglial inflammation and affect neuronal function and viability. In Aim 2, we will establish the role of medin in modulating hypoxic neurovascular unit injury. We will also test whether NLGM1 could protect against hypoxic injury to cellular components of the neurovascular unit using the 3D chip model and perform pilot investigation to test whether NLGM1 can protect mice against hypoxic injury from middle cerebral artery occlusion. Using novel cellular and human tissue models developed by our group, the proposal could impact our fundamental understanding of the early genesis of VaD, identify and characterize medin as a novel treatment target and validate NLGM1 as a novel therapeutic option.