Neuroimmunology of AD and CAA with focus on innate immunity and lymphatics

AD 和 CAA 的神经免疫学，重点关注先天免疫和淋巴系统

• 批准号: 10674670
• 负责人: Jonathan Kipnis
• 金额: $ 306.33万
• 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/10674670
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Apolipoprotein E; Area; Basic Science; Bioinformatics; Biology; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Brain Diseases; Cell Communication; Cells; Central Nervous System; Cerebral Amyloid Angiopathy; Cerebrospinal Fluid; Cerebrovascular system; Cholesterol Homeostasis; Collaborations; Collection; Complex; Data; Dementia; Discipline; Disease; Disease Progression; Economic Burden; Engraftment; Event; Excision; Functional disorder; Future; High Density Lipoproteins; Human; Image; Immune; Immune Targeting; Immune system; Immunologist; Immunotherapy; Impaired cognition; Innate Immune Response; Innate Immune System; Intercellular Fluid; Knowledge acquisition; Leptomeninges; Link; Lymphatic; Macrophage; Meningeal lymphatic system; Microglia; Mission; Myeloid Cells; National Institute on Aging; Natural Immunity; Nerve Degeneration; Neurodegenerative Disorders; Neuroimmune; Neurons; Neurosciences; Operative Surgical Procedures; Pathologic; Pathology; Pathway interactions; Patients; Persons; Phagocytosis; Population; Probability; Proteins; Publications; Research; Role; Route; SYK gene; Senile Plaques; Severity of illness; Signal Transduction; TREM2 gene; Technology; Therapeutic; Transgenic Mice; Transplantation; Vascular Diseases; abeta accumulation; age related; beta amyloid pathology; blood-brain barrier function; brain endothelial cell; clinical translation; cost; cranium; fluid flow; healing; imaging approach; in vivo; innovation; interdisciplinary approach; intravital imaging; lymphatic drainage; misfolded protein; multidisciplinary; neglect; neuroimmunology; new therapeutic target; novel; novel therapeutic intervention; pre-clinical; prevent; programs; protein aggregation; synergism; therapeutic target; tool; wasting

Project Summary/Abstract Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) are significant contributors to age-related dementia and a major economic burden. Current strategies to alleviate AD and CAA pathology and associated cognitive decline are largely ineffective, necessitating the need for additional therapeutic avenues to be explored, particularly with a multi-disciplinary team able to achieve a holistic understanding of vascular, neuronal, and immune events that underlie disease progression. One promising strategy is the augmentation of clearance pathways – including microglia/macrophage phagocytosis of Ab and meningeal lymphatic drainage of cerebral spinal fluid (CSF) - that facilitate the removal of toxic, misfolded protein aggregates that represent pathological hallmarks of AD brains. While the vast majority of prior research has focused on parenchymal Ab pathology and microglial functions, many patients also display CAA, contributing to vascular dysfunction, and implicating a role for parenchymal border macrophages (PBMs; perivascular and leptomeningeal, collectively). Thus, we will explore the complex interactions between the meningeal lymphatic system, CSF flow, PBMs, and parenchymal microglia in AD and CAA. The overall hypothesis of this PPG is that neuroimmune events, particularly aspects of the innate immune system and meningeal lymphatics, underlie AD and CAA pathology. We further hypothesize that devising new therapeutic approaches, harnessing the functions of microglia, PBMs, and the meningeal lymphatics may represent novel targets to alleviate AD-related cognitive decline. In particular, we will explore how dysfunction in cholesterol metabolism, apoE, and downstream TREM2 signaling contribute to homeostatic functions or promote pathological roles of microglia, PBMs, and the meningeal lymphatics, precipitating Ab pathology. Working as a highly collaborative multidisciplinary team, we will utilize newly developed innovative tools to explore these hypotheses, including intra-vital imaging approaches, in-vivo microanalysis, new transgenic mouse lines and unique surgical approaches. The specific projects and cores are as follows: Project 1: Kipnis, PI: Parenchymal border macrophages in AD and CAA. Project 2: Holtzman, PI: CAA: Role of ApoE, innate immunity, and meningeal lymphatics. Project 3: Randolph, PI: Interplay between meningeal lymphatics, high-density lipoproteins and border macrophages in CAA and AD. Project 4: Colonna, PI: The protein tyrosine kinase Syk drives innate immune responses against AD. Core A: Administration (Kipnis, PI); Core B: Imaging and surgery core (Randolph, PI).

项目摘要/摘要 阿尔茨海默氏病（AD）和脑淀粉样血管病（CAA）是与年龄有关的重要贡献者 痴呆症和重大经济负担。当前减轻AD和CAA病理及相关的策略 认知能力下降在很大程度上是无效的，对于探索其他治疗途径所必需的必要 特别是在多学科团队中，可以对血管，神经元和 疾病进展的免疫事件。一种诺言策略是增加清除 途径 - 包括AB和脑膜淋巴引流的小胶质细胞/巨噬细胞吞噬作用 脊柱液（CSF） - 促进代表病理的有毒，错误折叠的蛋白质聚集体的去除 广告大脑的标志。尽管绝大多数先前的研究都集中在实质AB病理学和 小胶质功能，许多患者也表现出CAA，导致血管功能障碍并暗示角色 用于实质边界巨噬细胞（PBMS；周围和瘦脑脑）。那我们会的 探索脑膜淋巴系统，CSF流，PBM和副群体之间的复杂相互作用 AD和CAA中的小胶质细胞。该PPG的总体假设是神经免疫事件，尤其是方面 先天免疫系统和脑膜淋巴机，基础AD和CAA病理学。我们进一步 假设设计新的治疗方法，利用小胶质细胞，PBM和 脑膜淋巴药可能代表减轻与广告相关的认知下降的新靶标。特别是，我们会 探索胆固醇代谢，APOE和下游Trem2信号的功能障碍如何有助于 稳态功能或促进小胶质细胞，PBM和脑膜淋巴染的病理作用， 促进AB病理学。作为一个高度协作的多学科团队，我们将使用新的 开发了创新的工具来探索这些假设，包括重要的成像方法，体内 微分析，新的转基因小鼠系和独特的手术方法。特定的项目和核心是 如下：项目1：kipnis，PI：AD和CAA中的实质边界巨噬细胞。项目2：霍尔茨曼，PI： CAA：APOE，先天免疫和脑膜淋巴细胞的作用。项目3：Randolph，PI：之间的相互作用 CAA和AD中的脑膜淋巴细胞，高密度脂蛋白和边界巨噬细胞。项目4：Colonna， PI：蛋白酪氨酸激酶SYK驱动与AD的先天免疫复杂。核心A：管理（Kipnis， pi）;核心B：成像和手术核心（Randolph，PI）。