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

基本信息

批准号：
10551329
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
项目类别：
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/10551329
关键词：
Ablation Acceleration Adopted Adult Affect Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid Proteins Amyloid beta-Protein Amyloid deposition Anatomic Border Animal Disease Models Astrocytes Behavior Behavioral Blood Blood - brain barrier anatomy Blood Circulation Blood Vessels Blood capillaries Border Crossings Brain Cells Central Nervous System Cerebral Amyloid Angiopathy Cerebrovascular system Characteristics Cre driver Data Defect Deposition Development Endothelial Cells Endothelium Gene Deletion Gene Expression Generations Genetic Histocompatibility Antigens Class II Immune Impaired cognition Impairment Individual Inflammatory Kinetics Location MAF gene Macrophage Maintenance Memory Microglia Mouse Strains Mus Names Pathologic Pathology 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C imaging study impaired capacity improved macromolecule mouse model neural normal aging tool transcription factor unpublished works uptake young adult

项目摘要

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.

抽象的脑脉管系统的健康对于脑淀粉样血管病（CAA）至关重要淀粉样蛋白在血管上的蛋白质，在阿尔茨海默氏症患者中观察到疾病（AD）以及AD动物模型。有人提出中枢神经系统（CNS）巨噬细胞对于保持大脑清洁有毒沉积很重要。小胶质细胞是最丰富的中枢神经系统中的巨噬细胞。也有非微型巨噬细胞，在此应用中称为边界相关的巨噬细胞（BAM）。我们的中心假设是小胶质细胞，由于其实质性位置，使大脑从未使用的神经连接中清洁，而BAM（BAM都有周围位置，发挥相似的功能，但针对脉管系统。年轻人的BAM的主要人口（70-80％）小鼠由表达高水平CD206，lyve1，cd38和tim4的细胞组成，MHC水平较低 II类分子（CD206HI MHC IILO）。成像研究表明，这些细胞与血管系统，显示出注入血液循环中的大分子大分子的高能力。我们的数据表明，在老年小鼠以及带有CAA的小鼠中，BAMS的内吞容量受损。但是，这是在没有特定试剂的情况下，很难研究BAM的作用。我们已经开发了三只鼠标菌株，lyve1-cre x maf f/f，lysm-cre maf f/f和缺少CD206HI MHC IILO BAM的CSF1R-CRE MAF f/f 完整的小胶质室。这是第一个可用于特异性靶向血管的遗传工具大脑中的巨噬细胞。 CD206HI缺乏小鼠已经扩大了小鼠的脑脉管系统，并且 CAA小鼠模型中夸大的淀粉样蛋白沉积。因此，我们认为BAM对维持脉管系统，我们的遗传工具将有助于确定BAM的功能。