Cerebral amyloid angiopathy: Role of ApoE, innate immunity, and meningeal lymphatics

脑淀粉样血管病：ApoE、先天免疫和脑膜淋巴管的作用

• 批准号: 10674679
• 负责人: DAVID M. HOLTZMAN
• 金额: $ 62万
• 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/10674679
• 关键词: Abeta clearance; Ablation; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Amyloid deposition; Antibodies; Antibody Therapy; Apolipoprotein E; Area; Astrocytes; Blood Vessels; Blood flow; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular system; Collaborations; Deposition; Development; Diameter; Edema; Elderly; Excision; Fibroblasts; Gene Expression; Genetic; Genotype; Goals; Grant; Hemorrhage; High Density Lipoproteins; Hypercapnia; Image; Imaging Techniques; Immune; Immune response; Immune system; Immunotherapy; Impaired cognition; Impairment; Individual; Inflammation; Ischemia; Leptomeninges; Link; Liquid substance; Lymphatic; Lymphatic function; Macrophage; Meningeal; Meningeal lymphatic system; Methods; Microglia; Modeling; Mus; Myeloid Cells; Natural Immunity; Nerve Degeneration; Operative Surgical Procedures; Passive Immunotherapy; Pathogenesis; Pathologic; Pathology; Pericytes; Play; Population; Post-Translational Protein Processing; Reporting; Risk; Role; Senile Plaques; Smooth Muscle Myocytes; VEGFC gene; Vascular Diseases; Vascular Endothelial Growth Factor C; Vascular Smooth Muscle; abeta deposition; age related; amyloid pathology; amyloidogenesis; apolipoprotein E-4; arteriole; brain parenchyma; cell type; experimental study; improved; mouse model; neuroimmunology; response; side effect; single-cell RNA sequencing; transcriptome; vascular inflammation

Abstract: Project 2 will investigate the interplay of APOE genotype, innate immunity, and meningeal lymphatics on cerebral amyloid angiopathy (CAA) and the translational implications of modifying lymphatic function on passive immunotherapy of CAA. CAA occurs in ~90% of individuals who develop Alzheimer’s disease (AD) and can occur independently of AD. The pathological hallmarks of CAA are deposition of amyloid composed in the majority of cases of amyloid-β (Aβ) along small arteriole vessel walls of the cerebral vasculature and leptomeninges. CAA leads to loss of vascular smooth muscle cells, impaired vasoreactivity, hemorrhages, and ischemia resulting in cognitive impairment and transient ischemic episodes. CAA is also linked with edema and microhemorrhages that are common side effects observed with several anti-Aβ antibodies known as amyloid-related imaging abnormalities (ARIA). The mechanisms underlying the development of CAA are not well understood, but prior studies indicate that APOE genotype, perivascular fluid flux, and innate immune cells can all influence CAA pathology. Like AD, APOE4 increases the risk of developing CAA. Recently, we demonstrated that anti-apoE antibodies that target a form of apoE that co- deposits with vascular amyloid reduced CAA and improved vascular function. In the brain parenchyma, apoE is predominantly expressed by astrocytes and reactive microglia. Vascular-associated cells, such as perivascular macrophages (PVMs), pericytes, and the recently described fibroblast-like vascular leptomeningeal cells (VLMCs) are also reported to express apoE. ApoE produced by different cell types differ in their lipidation state and post-translational modifications which could suggest a cell-specific role for apoE in CAA or subsequent vascular dysfunction and inflammation. Recent studies by the Kipnis lab have shown important contributions of the meningeal lymphatic system to Aβ deposition in parenchymal and leptomeningeal plaques. Impaired clearance of Aβ from perivascular spaces may also contribute to the formation of CAA, although the role of the meningeal immune system and the meningeal lymphatics in CAA formation and pathogenesis is unexplored. We hypothesize that 1) apoE plays a multifaceted role in CAA formation by influencing perivascular Aβ seeding and clearance in part via the meningeal lymphatic system and perivascular immune cells, 2) the meningeal lymphatic system plays a key role in CAA formation; and 3) augmenting the meningeal lymphatic system will increase the efficacy of anti-apoE immunotherapy reduction of CAA. We propose these Aims: Aim 1: To determine effect of cell-type specific apoE expression on CAA and meningeal lymphatic function. Aim 2: To determine the role of meningeal lymphatics on CAA pathology and associated inflammation and vascular dysfunction. Aim 3: To determine the effect of lymphatic function on the efficacy of anti-apoE antibody treatment on CAA and vascular dysfunction. Project 2 will collaborate extensively with all Projects and Cores in this grant to accomplish these goals.

摘要：项目 2 将研究 APOE 基因型、先天免疫和脑膜的相互作用 淋巴管对脑淀粉样血管病（CAA）的影响以及改变淋巴管的转化意义 CAA 被动免疫治疗的作用 CAA 发生在约 90% 的阿尔茨海默病患者中。 CAA 的病理特征是淀粉样蛋白的沉积。 大多数情况下，β淀粉样蛋白（Aβ）沿着大脑小动脉血管壁组成 CAA 导致血管平滑肌细胞损失、血管反应性受损、 出血和缺血导致认知障碍和短暂性脑缺血发作也是 CAA。 与水肿和微出血有关，这是几种抗 Aβ 药物观察到的常见副作用 称为淀粉样蛋白相关成像异常（ARIA）的抗体。 CAA 的发展尚不清楚，但先前的研究表明 APOE 基因型、血管周围液体 与 AD 一样，APOE4 会增加患 CAA 的风险。 最近，我们证明了针对 apoE 形式的抗 apoE 抗体可以共同- 血管淀粉样蛋白沉积物可减少 CAA 并改善脑实质中的血管功能。 主要由星形胶质细胞和反应性小胶质细胞表达，例如血管周围细胞。 巨噬细胞 (PVM)、周细胞和最近描述的成纤维细胞样血管软脑膜细胞 据报道，VLMC 也表达不同细胞类型产生的 ApoE，其脂化状态不同。 和翻译后修饰，这可能表明 apoE 在 CAA 或后续中具有细胞特异性作用 Kipnis 实验室最近的研究显示了血管功能障碍和炎症的重要贡献。 脑膜淋巴系统 Aβ 在实质和软脑膜斑块中沉积。 Aβ 从血管周围间隙的清除也可能有助于 CAA 的形成，尽管 Aβ 的作用 脑膜免疫系统和脑膜淋巴管在CAA形成和发病机制中的作用尚未探索。 我们发现 1) apoE 通过影响血管周围 Aβ 在 CAA 形成中发挥多方面的作用 部分通过脑膜淋巴系统和血管周围免疫细胞进行播种和清除，2) 脑膜淋巴系统在 CAA 形成中发挥关键作用；3) 增强脑膜； 淋巴系统将增加抗apoE免疫疗法减少CAA的疗效。 这些目标： 目标 1：确定细胞类型特异性 apoE 表达对 CAA 和脑膜淋巴管的影响 目标 2：确定脑膜淋巴管对 CAA 病理学及相关的作用。 目的 3：确定淋巴功能对炎症和血管功能障碍的影响。 项目2将主要与所有人合作进行抗apoE抗体治疗CAA和血管功能障碍。 本次拨款中的项目和核心旨在实现这些目标。