Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202-9037.
Institute of Neuroimmune Pharmacology and Department of Biological Sciences, Seton Hall University, South Orange, New Jersey 07079.
J Neurosci. 2021 Dec 15;41(50):10365-10381. doi: 10.1523/JNEUROSCI.1475-21.2021. Epub 2021 Nov 11.
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. 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.
神经毒性 HIV-1 病毒蛋白是导致 HIV 相关神经认知障碍（HAND）的原因之一，HAND 的发病率仍然很高（30-50%），且尚无有效的治疗方法。雌激素是一种已知的神经保护剂；然而，雌激素对不同类型雌激素受体的作用机制尚不完全清楚。在这项研究中，我们确定了天然非雌性化雌激素 17α-雌二醇（17αE2）通过何种机制以及在何种程度上对 HIV-1 gp120 诱导的神经元损伤提供神经保护作用。内溶酶体对于神经元功能很重要，而内溶酶体功能障碍会导致 HAND 和其他神经退行性疾病。在海马神经元中，雌激素受体 α（ERα）定位于内溶酶体，17αE2 使内溶酶体酸化。敲低 ERα 或过表达一种缺乏内溶酶体定位的 ERα 突变体，可阻止 17αE2 诱导的内溶酶体酸化。此外，17αE2 诱导的树突棘密度增加依赖于 ERα 的内溶酶体定位。用 17αE2 预处理可防止 HIV-1 gp120 诱导的内溶酶体去酸化和树突棘减少；这种保护作用依赖于 ERα 的内溶酶体定位。在雄性 HIV-1 转基因大鼠中，我们发现 17αE2 治疗可防止内溶酶体增大和树突棘减少的发生。我们的研究结果表明，17αE2 通过一种新型的内溶酶体依赖性途径发挥 ERα 介导的神经保护作用，这一发现可能为 HAND 的治疗策略的发展提供新的思路。膜结合雌激素受体（ERs）的核外存在是雌激素增强认知和突触功能的基础。雌激素受体亚型 ERα 存在于内溶酶体上，在 17αE2 对内溶酶体和树突棘的增强作用中发挥关键作用。这些发现为雌激素的神经保护作用提供了新的见解。此外，17αE2 可防止 HIV-1 gp120 诱导的内溶酶体功能障碍和树突棘减少，而 17αE2 的这些保护作用是通过 ERα 的内溶酶体定位介导的。这些发现为开发 17αE2 作为治疗 HIV 相关神经认知障碍的策略提供了依据。
