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

项目摘要/摘要 阿尔茨海默病(AD)和脑淀粉样血管病(CAA)是与年龄相关的重要因素 痴呆症和主要的经济负担。减轻AD和CAA病理及相关疾病的当前策略 认知能力下降在很大程度上是无效的，需要探索更多的治疗途径， 尤其是一个多学科团队，能够全面了解血管、神经元和 免疫事件是疾病发展的基础。一个有希望的战略是扩大清关。 小胶质细胞/巨噬细胞吞噬抗体和脑膜淋巴引流的途径 脊髓液(CSF)-有助于去除代表病理性的有毒、错误折叠的蛋白质聚集体 阿尔茨海默病大脑的特征。虽然之前的绝大多数研究都集中在实质抗体的病理学和 小胶质细胞功能，许多患者还表现为CAA，导致血管功能障碍，并牵涉到一个作用 实质边缘巨噬细胞(PBMs；统称为血管周围和软脑膜)。因此，我们将 探索脑膜淋巴系统、脑脊液流量、外周血巨噬细胞和脑实质之间的复杂相互作用 AD和CAA中的小胶质细胞。PPG的总体假设是神经免疫事件，特别是方面 先天性免疫系统和脑膜淋巴管是AD和CAA病理的基础。我们进一步 假设设计新的治疗方法，利用小胶质细胞、外周血巨噬细胞和 脑膜淋巴管可能是缓解AD相关认知功能下降的新靶点。特别是，我们将 探索胆固醇代谢、载脂蛋白E和下游TREM2信号通路的功能障碍是如何导致 小胶质细胞、外周血巨噬细胞和脑膜淋巴管的稳态功能或促进病理作用， 沉淀抗体病理学。作为一个高度协作的多学科团队，我们将利用新的 开发了探索这些假说的创新工具，包括活体内成像方法 微量分析、新的转基因小鼠品系和独特的手术方法。具体的项目和核心是 项目1：Kipnis，PI：AD和CAA中的实质边缘巨噬细胞。项目2：霍尔兹曼，少年派： CAA：载脂蛋白E、先天免疫和脑膜淋巴管的作用。项目3：伦道夫，少年派： CAA和AD的脑膜淋巴管、高密度脂蛋白和边缘巨噬细胞。项目4：科隆娜， PI：蛋白酪氨酸激酶Syk驱动对AD的先天免疫反应。核心A：行政管理(基普尼斯， PI)；核心B：成像和外科核心(伦道夫，PI)。

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).