Interstitial fluid flow in Alzheimer's Disease Progression

项目摘要 阿尔茨海默病是一种毁灭性的疾病，其特点是认知能力下降。这一下降背后的原因是 目前尚不清楚，但已知淀粉样蛋白β(Aβ)在大脑中的聚集和积聚有助于 不断恶化的认知缺陷。最近，人们发现大脑中体液流动的主要介质 与淀粉样蛋白β的清除有关，包括淋巴系统、脑膜淋巴管和 血管系统。通过这些途径中任何一条途径的液体流量减少都会恶化Aβ和认知能力的积累 这种疾病的小鼠模型存在缺陷。散装通道对于了解总体清除非常重要 然而，大脑并不能让我们洞察潜在的细胞或组织层面的机制。间隙 液体流动是细胞周围组织内的流动，与每个细胞表面相互作用。这些相互作用可能导致 在下游细胞信号的变化中，诱导激活、炎症级联和细胞迁移。在……里面 脑癌，由于肿瘤体积中间质压力的增加而导致间质液体流量增加 与周围脑组织相对正常的压力，或肿瘤微环境对接。在我们的 在格兰特之前，我们专注于脑癌间质血流的增加，以确定其潜在的机制。 这种流动中介的入侵。为了研究间质液体流动如何影响脑癌细胞的侵袭，我们 已经开发出在体外和体内检测流体流动响应的方法，包括体外多细胞组织 工程系统和活体成像方法。在AD中，尽管流量可能会减少，但相同的分子 而且，由于其流动敏感性，可能涉及到机理。因此，在此应用程序中，我们将直接在 应用活体成像技术对阿尔茨海默病小鼠模型体内间质血流的测量。使用这些信息，我们 我们将建立人类和小鼠健康和阿尔茨海默病的神经胶质微环境的体外模型 细胞识别干扰素在Aβ的分泌、积聚和构图中的作用以及不同的作用 A型β和IFF对细胞健康的影响。最后，我们将确定一种独特的分子在癌症中的作用 但在星形胶质细胞和小胶质细胞上表达，S1PR3，在介导AD表型并确定是否有 有益于治疗上痛苦或拮抗这种受体，以减轻认知障碍。总而言之，这些 报告将推进减轻阿尔茨海默病间质血流及其影响的重要性和策略 并提供了在细胞水平上进一步研究流动的影响的方式。了解 间质血流的影响最终可能有助于预测、诊断和治疗阿尔茨海默病。

Project Summary Alzheimer's Disease is a devastating disease marked by cognitive decline. The reasons underlying this decline are still unclear, but it is known that Amyloid β (Aβ) aggregation and accumulation in the brain contributes to worsening cognitive deficits. Recently, it has been identified that major mediators of bulk fluid flow in the brain are implicated in the clearing of Amyloid β, including the glymphatic system, the meningeal lymphatics, and the blood vasculature. Decreased fluid flow via any of these routes can worsen accumulation of Aβ and cognitive deficits in murine models of the disease. Bulk pathways are important for understanding overall clearance from the brain, however, it does not give us insight into the underlying cellular or tissue-level mechanisms. Interstitial fluid flow is the flow within tissue around the cells, interacting with each cell surface. These interactions can result in downstream changes to cell signaling inducing activation, inflammatory cascades, and cellular migration. In brain cancer, increased interstitial fluid flow develops due to the increase in interstitial pressure in the tumor bulk interfacing with the relatively normal pressure of the surrounding brain tissue, or tumor microenvironment. In our prior grant, we focused on this increased interstitial flow in brain cancer to identify the mechanisms underlying this flow-mediated invasion. To examine how interstitial fluid flow affects the invasion of brain cancer cells, we have developed in vitro and in vivo methods to examine fluid flow responses including multicellular in vitro tissue engineered systems and in vivo imaging methods. In AD, though flow may be decreasing, the same molecules and mechanisms may be involved due to their flow sensitivity. Thus, in this application, we will conduct direct in vivo measurements of interstitial flow using intravital imaging in mouse models of AD. Using this information we will build our in vitro models of the neuro-glial microenvironment with human and mouse healthy and AD-affected cells to identify the role of IFF in secretion, accumulation, and patterning of Aβ as well as the effect of different types of Aβ and IFF on cellular health. Last, we will determine the role of a unique molecule identified in cancer but expressed on astrocytes and microglia, S1PR3, in mediating the AD phenotype and determine if there is benefit to therapeutically agonizing or antagonizing this receptor to mitigate cognitive deficits. Altogether, these reports will advance the importance and strategies for mitigating interstitial flow and its effects in Alzheimer's Disease and offer modalities by which to study further effects of flow at the cellular level. Understanding the impact of interstitial flow may ultimately help predict, diagnose, and treat Alzheimer's Disease.