The role of brain border-associated macrophages in aging and cerebral amyloid angiopathy

摘要 脑血管系统的健康对于由沉积引起的脑淀粉样血管病(CAA)是至关重要的 淀粉样蛋白进入血管，在阿尔茨海默氏症患者中观察到很高的比例 疾病(AD)，以及在AD动物模型中。已有研究提出，中枢神经系统(CNS) 巨噬细胞对于保持大脑中有毒物质的清洁非常重要。小胶质细胞是最丰富的 中枢神经系统内的巨噬细胞。也有非小胶质巨噬细胞，在本应用中称为 边界相关巨噬细胞(BAM)。我们的中心假设是小胶质细胞，由于它的实质 位置，使大脑免受未使用的神经连接的影响，而BAM，有血管周围的位置， 发挥类似的功能，但目标是血管系统。青壮年BAM优势人群(70-80%) 小鼠由高水平表达CD206、LYVE1、CD38和Tim4以及低水平MHC的细胞组成 第二类分子(CD206HI、MHC、IiLO)。成像研究表明，这些细胞与 血管系统，显示出高容量的内吞大分子注入血液循环。 我们的数据显示，BAMS的内吞能力在老年小鼠和CAA小鼠中都受到了损害。然而，它是， 如果没有特定试剂，很难研究BAMS的作用。我们已经培育出三只小鼠 菌株，LYVE1-Cre X Maf/f，LysM-Cre Maf/f，和CSF1R-Cre Maf/f，缺乏CD206HI MHC Iio BAMS，但有 一个完整的小胶质细胞隔室。这是第一个可用于特定靶向血管周围的基因工具。 大脑中的巨噬细胞。CD206HI BAM缺陷小鼠扩大了小鼠的脑血管系统， CAA小鼠模型中淀粉样蛋白的过度沉积。因此，我们认为BAM对于 维持血管系统，我们的遗传工具将有助于阐明BAM的功能。

Abstract The health of the brain vasculature is essential for Cerebral amyloid angiopathy (CAA) results from the deposition of amyloid proteins onto blood vessels, and is observed in a very high percentage of patients with Alzheimer’s disease (AD), as well as in AD animal models. It has been proposed that central nervous system (CNS) macrophages are important in keeping the brain clean of toxic depositions. Microglia are the most abundant macrophages in the CNS. There are also non-microglial macrophages, which in this application are called Border-Associated macrophages (BAM). Our central hypothesis is that microglia, due to its parenchymal location, keeps clean the brain from unused neural connection, while BAM, which have a perivascular location, exert similar functions but targeting the vasculature. The dominant population (70-80%) of BAM in young adult mice is comprised of cells that express high levels of CD206, Lyve1, CD38 and Tim4, and low levels of MHC class II molecules (CD206HI MHC IILO). Imaging studies show that these cells are tightly associated with the blood vasculature, displaying a high capacity to endocytose macromolecules injected into the blood circulation. Our data show that BAMs’ endocytic capacity is impaired in aged mice as well as mice with CAA. It is, however, difficult to study the role of BAMs without the availability of specific reagents. We have developed three mouse strains, Lyve1-Cre X Maf f/f, LysM-Cre Maf f/f, and Csf1r-Cre Maf f/f that lacks CD206HI MHC IILO BAMs but have an intact microglial compartment. This is the first genetic tool that can be used to specifically target perivascular macrophages in the brain. CD206HI BAM-deficient mice have expanded brain vasculature in your mice, and exaggerated amyloid deposition in a mouse model of CAA. We therefore believe that BAM are important to maintain the vasculature, and that our genetic tool will be useful in clarifying BAM’s function.