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：
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
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/10367690
关键词：
Acceleration Adopted Adult Affect Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos 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improved macromolecule macrophage mouse model normal aging relating to nervous system tool transcription factor unpublished works uptake young adult

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.

抽象的脑血管系统的健康对于沉积引起的脑淀粉样血管病 (CAA) 至关重要淀粉样蛋白沉积在血管上，并且在阿尔茨海默病患者中观察到的比例非常高疾病（AD）以及 AD 动物模型中，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物很重要。小胶质细胞数量最多。 CNS 中还存在非小胶质细胞巨噬细胞，在本申请中称为这些巨噬细胞。我们的中心假设是小胶质细胞，由于其实质。位置，使大脑远离未使用的神经连接，而 BAM 位于血管周围，发挥相似的功能，但针对年轻成人中 BAM 的主要群体（70-80%）。小鼠由表达高水平 CD206、Lyve1、CD38 和 Tim4 以及低水平 MHC 的细胞组成 II 类分子 (CD206HI MHC IILO) 成像研究表明这些细胞与血管系统，表现出内吞注入血液循环的大分子的高能力。我们的数据表明，老年小鼠以及患有 CAA 的小鼠中 BAM 的内吞能力受到损害。如果没有特定试剂，很难研究 BAM 的作用。我们培育了三只小鼠。菌株 Lyve1-Cre X Maf f/f、LysM-Cre Maf f/f 和 Csf1r-Cre Maf f/f 缺乏 CD206HI MHC IILO BAM，但具有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 CD206HI BAM 缺陷小鼠的脑血管系统有所扩大，并且因此，我们认为 BAM 对 CAA 小鼠模型中的淀粉样蛋白沉积很重要。维持脉管系统，我们的遗传工具将有助于阐明 BAM 的功能。