Identifying and Correcting Dementia-Associated Changes in the Blood-Brain Barrier

迟发性神经退行性疾病，如阿尔茨海默病（AD），影响超过700万人 美国人，相关的医疗费用目前每年达到数千亿美元（以及 不断上升）。已知AD的病理学涉及比神经元更多的细胞类型。 海马体和皮层。构成脑血管系统的细胞，包括内皮细胞， 周细胞、星形胶质细胞和平滑肌细胞在维持健康和 大脑中的疾病特别是，内皮细胞的许多特性，包括它们在建立内皮细胞中的作用， 血脑屏障（blood-brain barrier，BBB）是血脑屏障的重要组成部分，它向脑组织输送营养物质，调节神经干细胞的增殖 细胞，对大脑正常功能至关重要。我们实验室和其他实验室的研究表明， 血管即使在受损后也可以恢复，这表明了治疗的新策略。 通过改善脑血管系统的完整性来治疗神经退行性疾病。在本书详细介绍的实验中， 应用程序，我们建议识别和纠正脑血管细胞内的过程， 已知会影响阿尔茨海默氏症和其他痴呆症。我们的一些工作是基于 认识到衰老是痴呆症的主要危险因素， 脉管系统作为全面了解衰老相关变化的一步， 我们的实验室最近发表了一项大型单细胞RNAseq研究，比较了年轻和老年小鼠的大脑。 在这里，我们建议利用我们对定义衰老过程的基因表达变化的了解， 确定对脑血管功能和BBB维持至关重要的细胞和分子因子， AD的小鼠模型。首先，我们将测试几种不同的假设， AD脑血管缺陷的基础。令人惊讶的是，最近的文献表明，其中一些 变化由可溶性因子介导，并且可能是可逆的。为了更详细地探讨这种可能性，我们 将利用我们对分泌因子介导的细胞-细胞相互作用的CNS网络的了解， AD脉管系统中发生的潜在可纠正的变化。最后，我们将利用我们实验室的专业知识， 诱导的多能干细胞（iPSC）以采用BBB的体外模型。这个体外平台将为 作为推定老化的体内机制评估的重要补充方法，或 人类脑血管细胞中的年轻化因子。与此同时，我们建议修改目前在 体外系统，应提高其能力，重演的性质，在体内血脑屏障。我们提议的 研究试图鉴定和验证脑血管系统的新调节剂，并阐明脑血管系统的功能是如何发挥的。 这些调节剂在痴呆中BBB的维持或降解中起作用。

Late onset neurodegenerative diseases, such as Alzheimer’s disease (AD), affect more than 7 million Americans, with the associated healthcare costs currently reaching hundreds of billions of dollars per year (and constantly rising). It is known that the pathology of AD involves many more cell types than the neurons of the hippocampus and cortex. The cells that comprise the brain vasculature, including the endothelial cells, pericytes, astrocytes and smooth muscle cells are critically important in maintaining the balance of health and disease in the brain. In particular, many properties of the endothelial cells, including their roles in establishing the blood-brain barrier (BBB), delivering nutrients to the brain, and regulating the proliferation of neural stem cells, are essential to proper brain function. Studies from our lab and others have demonstrated that brain vasculature can be restored even after it has been damaged, suggesting new strategies for treating neurodegenerative disorders via improving the integrity of brain vasculature. In experiments detailed in this application, we propose to both identify and correct processes within the cells of the brain vasculature that are known to be affected in Alzheimer’s disease and other dementias. Some of our work is based on the acknowledgement that aging is the major risk factor for dementia and is also characterized by declining vasculature. As a step toward obtaining a comprehensive understanding of aging-associated changes in the brain, our lab recently published a large single-cell RNAseq study comparing young and old mouse brains. Here, we propose to exploit our knowledge of the gene expression changes that define the aging process to identify cellular and molecular factors critical to brain blood vessel function and the maintenance of the BBB in a mouse model of AD. First, we will test several different hypotheses concerning the cellular and molecular bases for the vascular defects in the AD brain. Surprisingly, recent literature suggests that some of these changes are mediated by soluble factors and may be reversible. To explore this possibility in greater detail, we will use our knowledge of the CNS network of cell-cell interactions mediated by secreted factors to identify potentially correctable changes that occur in AD vasculature. Finally, we will use our lab’s expertise in human induced pluripotent stem cells (iPSCs) to employ an in vitro model of the BBB. This in vitro platform will serve as an important complementary approach to the in vivo mechanistic evaluation of putative aging or rejuvenation factors in human brain vascular cells. At the same time, we propose modifications of the current in vitro system that should improve its ability to recapitulate properties of the in vivo BBB. Together, our proposed studies seek to identify and validate new modulators of brain vasculature and to elucidate how the functions of these modulators play a role in the maintenance or degradation of the BBB in dementia.