Estrogen receptor (ER) ? expression in oligodendrocytes is required for attenuation of clinical disease by an ER beta ligand

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-11, Vol.110 (47), p.19125-19125
• Main Authors: Khalaj, Anna J, Yoon, JaeHee, Nakai, Jaspreet, Winchester, Zachary, Moore, Spencer M, Yoo, Timothy, Martinez-Torres, Leonardo, Kumar, Shalini, Itoh, Noriko, Tiwari-Woodruff, Seema Kaushalya
• Format: Article
• Language: English
• ISSN: 0027-8424

Treatment of experimental autoimmune encephalomyelitis (EAE) mice with the estrogen receptor (ER) beta ligand diarylpropionitrile (DPN) has been shown to have neuroprotective effects via stimulation of endogenous myelination. The direct cellular mechanisms underlying the effects of this ER beta ligand on the central nervous system are uncertain because different cell types in both the peripheral immune system and central nervous system express ERs. ER beta is the target molecule of DPN because DPN treatment fails to decrease EAE clinical symptoms in global ER beta -null mice. Here we investigated the potential role of ER beta expression in cells of oligodendrocyte (OL) lineage in ER beta ligand-mediated neuroprotection. To this end, we selectively deleted ER beta in OLs using the well-characterized Cre-loxP system for conditional gene knockout (CKO) in mice. The effects of this ER beta CKO on ER beta ligand-mediated neuroprotective effects in chronic EAE mice were investigated. ER beta CKO in OLs prevented DPN-induced decrease in EAE clinical disease. DPN treatment during EAE did not attenuate demyelination, only partially improved axon conduction, and did not activate the phosphatidylinositol 3-kinase/serine-threonine-specific protein kinase/mammalian target of rapamycin signaling pathway in ER beta CKO mice. However, DPN treatment significantly increased brain-derived neurotrophic factor levels in ER beta CKO mice. These findings demonstrate that signaling through ER beta in OLs is essential for the beneficial myelination effects of the ER beta ligand DPN in chronic EAE mice. Further, these findings have important implications for neuroprotective therapies that directly target OL survival and myelination.