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 包括阿尔茨海默病（AD）在内的许多中枢神经系统（CNS）疾病与阿尔茨海默病相关。 免疫系统功能紊乱血管周围和软脑膜巨噬细胞群（我们认为 现在统称为实质边缘巨噬细胞或PBM），位于 中枢神经系统实质，并与脑脊液（CSF）相互作用。我们的初步数据显示， PBM的药理学或遗传学消融导致血管运动受损和CSF动力学破坏。 此外，我们的研究结果表明，PBMs的耗竭导致血管周围细胞外基质的积累， (ECM)蛋白质和血管周围空间的收缩。老年小鼠的特征是CSF受损 这与PBM表型的改变有关（Lyve 1表达减少和 MHCII）。最令人惊讶的是，向CSF中注射巨噬细胞集落刺激因子（M-CSF）逆转了 年龄对CSF流量的影响，进一步将PBM功能障碍与CSF动力学异常联系起来。我们有 最近表明，头骨骨髓提供硬脑膜骨髓细胞，并且在受伤后或受伤期间 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周转。鉴于建设和平委员会的战略位置， 头骨骨髓细胞对它们的更新的贡献，在这个建议中，我们将重点放在PBM上， 了解他们在AD中的角色。我们推测，衰老促进PBM的激活， 获得促炎表型，导致ECM的积聚，从而导致血管周围 不太允许流动的空间和CSF动力学的总体损害。这反过来又有助于 淀粉样蛋白从脑实质中清除受损，并沿血管沿着，加重 实质淀粉样变性和沉淀性脑淀粉样血管病（CAA）。我们进一步假设， PBM的治疗性操作可以改善CSF动力学，并至少在一定程度上减轻 与AD和CAA相关的病理学。在这个项目中，我们将密切互动和合作，与其他 该计划的项目，以及手术和成像的核心。我们假设的证明将引入一个新的 参与者，即PBMs，在AD和CAA病理生理学。同样重要的是，它可能预示着 新的治疗靶点和干预措施，可以延迟发病，甚至改善正在进行的 衰老相关神经系统疾病的病理生理学。