Abstract
Neurotoxic HIV-1 viral proteins contribute to the development of HIV-associated neurocognitive disorder (HAND), the prevalence of which remains high (30-50%) with no effective treatment available. Estrogen is a known neuroprotective agent; however, the diverse mechanisms of estrogen action on the different types of estrogen receptors is not completely understood. In this study, we determined the extent to which and mechanisms by which 17α-estradiol (17αE2), a natural less-feminizing estrogen, offers neuroprotection against HIV-1 gp120-induced neuronal injury. Endolysosomes are important for neuronal function, and endolysosomal dysfunction contributes to HAND and other neurodegenerative disorders. In hippocampal neurons, estrogen receptor α (ERα) is localized to endolysosomes and 17αE2 acidifies endolysosomes. ERα knockdown or overexpressing an ERα mutant that is deficient in endolysosome localization prevents 17αE2-induced endolysosome acidification. Furthermore, 17αE2-induced increases in dendritic spine density depend on endolysosome localization of ERα. Pretreatment with 17αE2 protected against HIV-1 gp120-induced endolysosome deacidification and reductions in dendritic spines; such protective effects depended on endolysosome localization of ERα. In male HIV-1 transgenic rats, we show that 17αE2 treatment prevents the development of enlarged endolysosomes and reduction in dendritic spines. Our findings demonstrate a novel endolysosome-dependent pathway that governs the ERα-mediated neuroprotective actions of 17αE2, findings that might lead to the development of novel therapeutic strategies against HAND.SIGNIFICANCE STATEMENT Extranuclear presence of membrane-bound estrogen receptors (ERs) underlie the enhancing effect of estrogen on cognition and synaptic function. The estrogen receptor subtype ERα is present on endolysosomes and plays a critical role in the enhancing effects of 17αE2 on endolysosomes and dendritic spines. These findings provide novel insight into the neuroprotective actions of estrogen. Furthermore, 17αE2 protected against HIV-1 gp120-induced endolysosome dysfunction and reductions in dendritic spines, and these protective effects of 17αE2 were mediated via endolysosome localization of ERα. Such findings provide a rationale for developing 17αE2 as a therapeutic strategy against HIV-associated neurocognitive disorders.