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

摘要 血管性痴呆（VaD）是痴呆的第二大常见原因，也是最常见的原因。 患者年龄< 74岁。在老龄化的退伍军人中，痴呆症是一个关键的卫生保健问题， 7.3%的退伍军人≥ 65岁1。为了预防或管理VaD，了解其早期病理生理学至关重要， 特别是学习血管疾病和炎症，一个发生在VaD几十年前的过程， 调节神经炎症和神经变性。我们已经确定并表征了一种新的假定的 血管老化剂，medin，最常见的人类淀粉样蛋白之一，发现在更大的数量 在VaD和阿尔茨海默病（AD）患者中，并且其可引起内皮功能障碍，促炎性 激活类似于心血管风险因子（CVRF），并加剧内皮细胞的缺氧损伤 （EC）。在血管疾病的后期，动脉粥样硬化和血栓栓塞性变化可导致缺血 以及脑组织缺氧或中风，这是第五大死亡原因。调查因素，如medin， 可能会加剧这种损伤，这将导致新的治疗目标。此外，我们还表明， 含有单唾液酸神经节苷脂的纳米脂质体（NLGM1，磷脂颗粒<100 nm） 缺氧和氧化应激诱导内皮功能障碍和血管炎症。基于这些初始 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， 功能和识别新的治疗靶点和干预，以减轻VaD中的缺氧损伤。在目标1中， 建立脑血管炎症调节神经炎症的机制， 神经变性在这里，我们将使用2D细胞，新的3D血管化脑器官芯片和离体 来自VaD、AD或正常认知的脑供体的侧支脑动脉，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 功能和可行性。目的2：建立Medin在缺氧神经血管单位调节中的作用 损伤我们还将测试NLGM1是否可以防止缺氧损伤的细胞成分， 神经血管单位使用3D芯片模型，并进行试点调查，以测试是否NLGM1可以保护 小鼠大脑中动脉缺血缺氧性损伤。使用新的细胞和人体组织模型 由我们小组开发的，该建议可能会影响我们对VaD早期起源的基本理解， 鉴定和表征作为新治疗靶点的medin，并验证NLGM1作为新的治疗选择。

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.