The Mechanisms of Estrogen Receptor Beta Ligand Mediated Neuroprotection

University Of California Los Angeles, Los Angeles CA

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Abstract

? DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and demyelination of the central nervous system (CNS). The most widely used animal model for MS is experimental autoimmune encephalomyelitis (EAE). EAE is initiated by Th1/Th17-mediated immune responses causing demyelination and axonal damage. Current MS treatments have immunomodulatory effects and reduce relapse rates in MS patients, but have modest effects on disability progression. There is a need to develop new treatments that are neuroprotective and understand their mechanisms to halt disability progression. Administration of estrogens and estrogen receptor (ER) specific-ligands in neurodegenerative disease models has neuroprotective effects. Specifically, our lab has shown that treatment with the ER?-ligand is neuroprotective during EAE by providing clinical disease protection, preserving neurons, preventing demyelination and promoting remyelination. With increasing evidence that ER? plays an important role in synaptic plasticity, improving memory, brain development and cognition, we focus on understanding the mechanisms of ER?-ligand treatment on neuroprotection. Recently, using a cell specific approach by creating conditional knockouts (CKO) of ER? in cells of the CNS, we shown that ER? expression on astrocyte and neurons do not play an important role for mediating neuroprotective effects of ER?-ligand treatment during EAE. In contrast, a subsequent study reported that oligodendrocytes may play a role, however, the mechanism remains unclear. This project will focus on investigating whether the neuroprotective effects of ER?-ligand treatment are mediated through immune cells of the CNS, microglial cells and dendritic cells (DCs). Microglial cells and DCs share similar phenotypes and lineage properties, however, they are located in different environments. Microglial cells are resident CNS immune cells and DCs reside near the boundaries of the brain, such as the choroid plexus and perivascular space. DCs have a specific marker CD11c to study them, although, recently it has been reported that activated microglial cells also express CD11c during EAE. Therefore, studying the function of these cells in vivo using one marker has been difficult to achieve. In this proposal, we will utilize the DCs marker, CD11c, for cell sorting and creating bone marrow chimeras to distinguish the effect of ER?-ligand treatment between CD11c+ microglial cells versus DCs. In addition, we understand the underlying mechanisms of ER? signaling in each cell type through immunofluorescence and confocal microscopy, flow cytometry and mRNA expression analyses.