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

点击翻译按钮获取中文摘要

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).