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)，影响着700多万人 美国人，相关的医疗费用目前达到每年数千亿美元(和 不断上升)。众所周知，阿尔茨海默病的病理涉及的细胞类型比神经元多得多。 海马体和皮质。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营养平衡方面至关重要 脑部疾病。特别是，内皮细胞的许多特性，包括它们在建立 血脑屏障(BBB)，将营养物质输送到大脑，调节神经干细胞的增殖 细胞，对正常的大脑功能是必不可少的。我们实验室和其他实验室的研究表明，大脑 血管系统即使在受损后也可以恢复，这就提出了新的治疗策略 通过改善脑血管系统的完整性来治疗神经退行性疾病。在本文件中详细介绍的实验中 应用，我们建议既识别和纠正脑血管细胞内的过程， 已知受到阿尔茨海默病和其他痴呆症的影响。我们的一些工作是基于 承认老龄化是痴呆症的主要风险因素，其特点也是衰老 脉管系统。作为全面了解衰老相关变化的一步 在大脑方面，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知识来 确定对脑血管功能和血脑屏障维持至关重要的细胞和分子因子 阿尔茨海默病的小鼠模型。首先，我们将检验关于细胞和分子的几种不同的假说 阿尔茨海默病大脑血管缺陷的基础。令人惊讶的是，最近的文献表明，其中一些 变化是由可溶性因子介导的，并且可能是可逆的。为了更详细地探讨这种可能性，我们 将利用我们对由分泌因子介导的中枢神经系统细胞-细胞相互作用网络的知识来识别 AD血管系统中可能发生的可纠正的变化。最后，我们将利用我们实验室在人类方面的专业知识 诱导多能干细胞(IPSCs)采用血脑屏障的体外模型。这个体外平台将服务于 作为体内衰老机制评估的重要补充方法 人脑血管细胞中的返老还童因子。同时，我们建议修改现行的 体外系统，应提高其概括体内血脑屏障特性的能力。一起，我们的建议 研究试图识别和验证新的脑血管调节因子，并阐明脑血管调节因子的功能 这些调节剂在痴呆患者血脑屏障的维持或降解中发挥作用。

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.