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

脑边界相关巨噬细胞在衰老和脑淀粉样血管病中的作用

• 批准号: 10367690
• 负责人: Juan Lafaille
• 金额: $ 63.68万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367690
• 关键词: Acceleration; Adopted; Adult; Affect; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid Proteins; Amyloid beta-Protein; Amyloid deposition; Anatomy; Animal Disease Models; Astrocytes; Behavior; Behavioral; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Blood capillaries; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular system; Characteristics; Cre driver; Data; Defect; Deposition; Development; Endothelial Cells; Endothelium; Gene Expression; Generations; Genetic; Histocompatibility Antigens Class II; Immune; Impaired cognition; Impairment; Individual; Inflammatory; Kinetics; Location; MAF gene; Maintenance; Memory; Microglia; Mouse Strains; Mus; Names; Neuraxis; Pathologic; Pathology; Patients; Pericytes; Physiological; Play; Population; Process; Proteins; Reagent; Regulation; Role; Running; Shapes; Stress; Testing; Tissues; abeta accumulation; aged; arteriole; behavior test; brain health; cell type; cognitive function; factor C; imaging study; impaired capacity; improved; macromolecule; macrophage; mouse model; normal aging; relating to nervous system; tool; transcription factor; unpublished works; uptake; young adult

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.

摘要 脑血管系统的健康是脑淀粉样血管病（CAA）的基础， 淀粉样蛋白沉积到血管上，在阿尔茨海默氏症患者中观察到的比例很高 疾病（AD），以及AD动物模型中。已经提出中枢神经系统（CNS） 巨噬细胞在保持大脑清除有毒沉积物方面是重要的。小胶质细胞是最丰富的 巨噬细胞在中枢神经系统。还有非小胶质细胞巨噬细胞，在本申请中称为 边界相关巨噬细胞（BAM）。我们的中心假设是，小胶质细胞，由于其实质 位置，保持清洁大脑从未使用的神经连接，而BAM，有一个血管周围的位置， 发挥类似的功能，但针对脉管系统。BAM的优势种群（70-80%）为青壮年 小鼠由表达高水平的CD 206、Lyve 1、CD 38和Tim 4以及低水平的MHC的细胞组成 II类分子（CD 206 HI MHC IILO）。成像研究表明，这些细胞与 血管系统，显示出高的内吞注射到血液循环中的大分子的能力。 我们的数据表明，BAM的内吞能力在老年小鼠和CAA小鼠中受损。然而， 在没有特定试剂的情况下，难以研究BAM的作用。我们开发了三种鼠标 菌株Lyve 1-Cre X Maf f f/f、LysM-Cre Maf f f/f和Csf 1 r-Cre Maf f f/f，其缺乏CD 206 HI MHC IILO BAM，但具有 一个完整的小胶质细胞区室这是第一个可用于特异性靶向血管周围的遗传工具 大脑中的巨噬细胞CD 206 HI BAM缺陷型小鼠在您的小鼠中具有扩张的脑血管， CAA小鼠模型中淀粉样蛋白沉积过度。因此，我们认为，巴卡拉OK设施对于 维持脉管系统，我们的遗传工具将有助于阐明BAM的功能。