Interplay between meningeal lymphatics, high-density lipoproteins and border macrophages in cerebral amyloid angiopathy

点击翻译按钮获取中文摘要

ABSTRACT – project 3 The Randolph lab studies vascular inflammation and has a long-standing interest in the egress of cells and molecules that impact chronic vascular diseases. With a track record in studying the trafficking of monocytes (and the cells they become), we later began studying the transit of apoA1-enriched high-density lipoprotein (HDLA1) through tissues. We demonstrated that liver-derived HDLA1 leaves most tissue parenchyma through lymphatics to mediate reverse cholesterol transport, a process whereby cholesterol from cells in various body organs is picked up by HDLA1 and returned to the liver for disposal in bile. Reverse cholesterol transport regulates macrophage phenotype in various diseases, as macrophages readily accumulate cholesterol. On the other hand, macrophages also efficiently transfer cholesterol to HDLA1 via the membrane transporter ABCA1 in a process called cholesterol efflux. If cholesterol efflux is impaired, for example from reduction of HDLA1, cholesterol accumulates in signaling domains at the plasma membrane to affect the phenotype and activation status of macrophages. Overall, macrophages and lymphatics provide two distinct means for tissue clearance of metabolites, debris, and other mediators--one via endocytosis or phagocytosis and the other via fluid transport--and HDLA1 bridges these mechanisms. We have developed and validated a knock-in mouse line expressing photoactivatable GFP linked to apoA1, to quantitatively track endogenous HDLA1 after photo- activating a tissue of interest. Although little HDLA1 crosses the blood-brain barrier to enter the brain, HDLA1 enters the meningeal interstitium. Indeed, preliminary data reveal that the HDLA1 can be tagged by shining 405 nm light on the thinned skullbone as the HDLA1 passes through the meninges. Phototagged meningeal HDLA1 reaches the blood circulation one hour later, but only under conditions when the meningeal draining lymphatic vasculature is intact. Epidemiological studies in cerebral amyloid angiopathy (CAA), a disease broadly associated with Alzheimer’s disease (AD) and characterized by A deposition in the adventitia of the penetrating and meningeal arterioles, identify HDLA1 levels as inversely correlated with cerebral hemorrhage associated with CAA. A connection between HDLA1 and CAA is directly supported by genetic and experimental therapeutic interventions in mice. However, detailed mechanistic studies to unravel how HDLA1 affects CAA have not been conducted. Using the 5XE4fl/fl murine model of CAA developed by the Holtzman laboratory, we will herein focus on unraveling the role of HDLA1 in CAA by coupling use of our HDLA1 phototag tool with approaches to interrogate its connection to lymphatic and blood flow (aim 1), to monocyte/macrophage phenotype (aim 2), and to disease progression overall (aim 3). We here will test the hypothesis that HDLA1 restrains CAA and that its meningeal transit is impaired during CAA. By contrast, in states of health, we propose that it functionally maintains meningeal interstitial flow into lymphatics by interacting with and governing the phenotype of meningeal macrophages, including parenchymal border macrophages (PBM).