Interstitial fluid flow in Alzheimer's Disease Progression

项目摘要 阿尔茨海默病是一种以认知能力下降为特征的毁灭性疾病。造成这种下降的原因是 目前尚不清楚，但已知β淀粉样蛋白（Aβ）在大脑中的聚集和积累有助于 认知缺陷恶化最近，已经确定脑中大量流体流动的主要介质 与淀粉样蛋白β的清除有关，包括胶质淋巴系统、脑膜炎细胞和 血管系统通过任何这些途径的液体流量减少都可能加重Aβ的积聚和认知功能障碍。 在疾病的小鼠模型中的缺陷。本体途径对于理解从 然而，它并没有让我们深入了解潜在的细胞或组织水平的机制。间质 流体流动是在细胞周围的组织内与每个细胞表面相互作用的流动。这些相互作用可能导致 在下游变化的细胞信号诱导激活，炎症级联反应，和细胞迁移。在 脑癌，由于肿瘤体积中的间质压力增加而导致间质液流量增加 与周围脑组织或肿瘤微环境的相对正常压力相连接。在我们 先前的拨款，我们专注于这种增加间质流在脑癌，以确定其机制 这种血流介导的入侵为了研究间质液流动如何影响脑癌细胞的侵袭，我们 已经开发了体外和体内方法来检查包括多细胞体外组织的流体流动响应 工程系统和体内成像方法。在AD中，虽然流量可能会减少，但相同的分子 并且由于它们的流动敏感性而可能涉及到机制。因此，在本申请中，我们将直接在 在AD小鼠模型中使用活体成像进行的间质流的体内测量。利用这些信息，我们 将建立我们的体外模型的神经胶质细胞微环境与人类和小鼠的健康和AD的影响 细胞，以确定IFF在Aβ分泌、积累和形成模式中的作用，以及不同的 Aβ和IFF类型对细胞健康的影响。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，介导AD表型，并确定是否有 有益于在治疗上激动或拮抗该受体以减轻认知缺陷。总之，这些 报告将推进减轻间质流的重要性和策略及其在阿尔茨海默氏症中的作用 疾病和提供模式，通过它来研究进一步的影响流在细胞水平上。了解 间质流的影响可能最终有助于预测，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.