Parenchymal border macrophages in AD and CAA

AD 和 CAA 中的实质边界巨噬细胞

• 批准号: 10674673
• 负责人: Jonathan Kipnis
• 金额: $ 62.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674673
• 关键词: Ablation; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloidosis; Antibodies; Biology; Blood Vessels; Bone Marrow; Bone Marrow Cells; Brain; Cells; Central Nervous System; Central Nervous System Diseases; Cerebral Amyloid Angiopathy; Cerebrospinal Fluid; Collaborations; Data; Deposition; Dichloromethylene Diphosphonate; Diffusion; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Functional disorder; Genetic; Image; Immune System Diseases; Impairment; Inflammatory; Injections; Injury; Invaded; Knock-in Mouse; Leptomeninges; Link; Liposomes; Location; Lymphatic; Macrophage; Macrophage Activation; Macrophage Colony-Stimulating Factor; Mediator; Meningeal lymphatic system; Messenger RNA; Methods; Microglia; Mus; Myeloid Cells; Natural Immunity; Nerve Degeneration; Neuroimmune; Operative Surgical Procedures; Pathology; Penetration; Phenotype; Physiology; Population; Process; Role; TREM2 gene; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Transplantation; Traumatic Brain Injury; Treatment Factor; Vaccination; abeta deposition; age related; aged; apolipoprotein E-4; brain parenchyma; cerebrospinal fluid flow; cranium; cytokine; driving force; glymphatic system; imaging approach; improved; lymphatic vessel; monocyte; mouse model; nervous system disorder; neuroimmunology; neuroinflammation; new therapeutic target; normal aging; novel; permissiveness; pharmacologic; prevent; programs; theories; therapeutic target; vasomotion

PROJECT SUMMARY Many diseases of the central nervous system (CNS), including Alzheimer’s disease (AD), are associated with immune system dysfunction. A population of perivascular and leptomeningeal macrophages (which we now collectively refer to as parenchymal-border macrophages, or PBMs), resides at the borders of the CNS parenchyma and interact with the cerebrospinal fluid (CSF). Our preliminary data indicate that pharmacological or genetic ablation of PBMs leads to impaired vasomotion and disrupted CSF dynamics. Moreover, our findings show that depletion of PBMs results in buildup of perivascular extracellular matrix (ECM) proteins and shrinkage of the perivascular space. Aged mice are characterized by impaired CSF dynamics and this is associated with an altered PBM phenotype (reduced Lyve1 expression and induction of MHCII). Most surprisingly, injection of macrophage colony-stimulating factor (M-CSF) into the CSF reversed the age-associated effects on CSF flow, further linking PBM dysfunction to abnormal CSF dynamics. We have recently showed that the skull bone marrow supplies dural myeloid cells, and that after injury or during neuroinflammation these cells can invade the CNS parenchyma. Our preliminary results demonstrate that skull bone marrow-derived monocytes also contribute to PBM turnover. Given the strategic location of the PBMs and the contribution of skull bone marrow cells to their renewal, in this proposal we will focus on PBMs to understand their roles in AD. We hypothesize that aging promotes the activation of PBMs and their acquisition of a pro-inflammatory phenotype, resulting in the build-up of ECM, thus leading to perivascular spaces less permissive to flow and an overall impairment of CSF dynamics. This in turn contributes to impaired amyloid clearance from the brain parenchyma and deposition along the vasculature, aggravating parenchymal amyloidosis and precipitating cerebral amyloid angiopathy (CAA). We further hypothesize that therapeutic manipulation of the PBMs may improve CSF dynamics and alleviate, at least to some extent, the pathology associated with AD and CAA. In this project we will closely interact and collaborate with other projects of the program, as well as the surgery and imaging core. Proof of our hypothesis will introduce a new player, namely PBMs, in AD and CAA pathophysiology. Not less importantly, it may herald the discovery of new therapeutic targets and interventions that can delay the onset or even improve the ongoing pathophysiology of devastating aging-associated neurological diseases.

项目概要 许多中枢神经系统 (CNS) 疾病，包括阿尔茨海默病 (AD)，都与 免疫系统功能障碍。 现在统称为实质边界巨噬细胞（PBM），位于 CNS 实质并与脑脊液 (CSF) 相互作用。 PBM 的药理学或基因消融会导致血管舒缩受损和脑脊液动力学破坏。 此外，我们的研究结果表明，PBM 的消耗会导致血管周围细胞外基质的堆积 (ECM) 蛋白和血管周围空间收缩是老年小鼠脑脊液受损的特征。 动力学，这与改变的 PBM 表型有关（Lyve1 表达减少和诱导 最令人惊讶的是，将巨噬细胞集落刺激因子（M-CSF）注射到脑脊液中可以逆转 年龄相关的脑脊液流量影响，进一步将 PBM 功能障碍与脑脊液动力学异常联系起来。 最近表明，颅骨骨髓供应硬脑膜骨髓细胞，并且在受伤后或期间 神经炎症这些细胞可以侵入中枢神经系统实质，我们的初步结果表明颅骨。 鉴于 PBM 的战略位置，骨髓来源的单核细胞也有助于 PBM 周转。 颅骨骨髓细胞对其更新的贡献，在本提案中，我们将重点关注 PBM 了解它们在 AD 中的作用。我们勇敢地承认，衰老会促进 PBM 及其活性的激活。 获得促炎表型，导致 ECM 积聚，从而导致血管周围 空间不太容易流动，从而导致脑脊液动力的整体受损。 大脑实质中淀粉样蛋白的清除受损以及沿着脉管系统的沉积，从而加重 实质淀粉样变性和诱发脑淀粉样血管病（CAA）。 PBM 的治疗操作可能会改善 CSF 动态并至少在一定程度上缓解 在这个项目中，我们将与其他人密切互动和合作。 该计划的项目以及手术和成像核心将引入新的证明。 同样重要的是，它可能预示着 AD 和 CAA 病理生理学中的重要角色，即 PBM。 新的治疗目标和干预措施可以延迟发病甚至改善正在进行的症状 破坏性衰老相关神经系统疾病的病理生理学。