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.

项目摘要 包括阿尔茨海默氏病（AD）在内的中枢神经系统（CNS）的许多疾病与 免疫系统功能障碍。血管周围和瘦脑膜巨噬细胞的人群（我们 现在，统称为副群巨噬细胞或PBMS）的住所 CNS实质并与脑脊液（CSF）相互作用。我们的初步数据表明 PBM的药理或遗传消融导致血管舒张症受损和CSF动力学破坏。 此外，我们的发现表明，PBM的耗竭会导致细胞内细胞外基质的积累 （ECM）蛋白质和血管周空间的收缩。老年小鼠的特征是CSF受损 动力学，这与PBM表型发生变化有关（Lyve1表达降低和诱导的诱导 MHCII）。最令人惊讶的是，将巨噬细胞刺激因子（M-CSF）注射到CSF中 与年龄相关的对CSF流动的影响，将PBM功能障碍与异常CSF动力学联系起来。我们有 最近表明，颅骨骨髓提供硬膜髓样细胞，并在受伤后或在 神经炎症这些细胞可以侵入CNS实质。我们的初步结果表明头骨 骨髓来源的单核细胞也有助于PBM营业额。鉴于PBM的战略位置和 颅骨骨髓细胞对其更新的贡献，在此提案中，我们将专注于PBMS 了解他们在广告中的作用。我们假设衰老促进了PBM及其的激活 获得促炎的表型，导致ECM的积累，从而导致血管周围 空间不太允许流动和CSF动力学的总体损害。这反过 大脑实质的淀粉样蛋白清除受损，沿脉管系统沉积，加剧 实质性淀粉样变性和沉淀大脑淀粉样血管病（CAA）。我们进一步假设 对PBM的治疗操作可能会改善CSF动力学，并至少在某种程度上减轻 与AD和CAA相关的病理学。在这个项目中，我们将密切互动并与其他 该计划的项目以及手术和成像核心。我们假设的证明将引入一个新的 玩家，即PBM，在AD和CAA病理生理学中。同样重要的是，它可以预示发现的发现 新的治疗靶标和干预措施，可以延迟发作甚至改善正在进行的 毁灭性衰老相关神经系统疾病的病理生理。