Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Nat Commun. 2023 Sep 28;14(1):6044. doi: 10.1038/s41467-023-41723-7.
Menopause is associated with cognitive deficits and brain atrophy, but the brain region and cell-specific mechanisms are not fully understood. Here, we identify a sex hormone by age interaction whereby loss of ovarian hormones in female mice at midlife, but not young age, induced hippocampal-dependent cognitive impairment, dorsal hippocampal atrophy, and astrocyte and microglia activation with synaptic loss. Selective deletion of estrogen receptor beta (ERβ) in astrocytes, but not neurons, in gonadally intact female mice induced the same brain effects. RNA sequencing and pathway analyses of gene expression in hippocampal astrocytes from midlife female astrocyte-ERβ conditional knock out (cKO) mice revealed Gluconeogenesis I and Glycolysis I as the most differentially expressed pathways. Enolase 1 gene expression was increased in hippocampi from both astrocyte-ERβ cKO female mice at midlife and from postmenopausal women. Gain of function studies showed that ERβ ligand treatment of midlife female mice reversed dorsal hippocampal neuropathology.
绝经与认知缺陷和脑萎缩有关，但大脑区域和细胞特异性机制尚未完全阐明。在这里，我们发现了一种性别激素与年龄的相互作用，即中年雌性小鼠失去卵巢激素，但不是在年轻时，会导致海马依赖性认知障碍、背侧海马萎缩以及星形胶质细胞和小胶质细胞激活伴突触丢失。在性腺完整的雌性小鼠中，选择性地在星形胶质细胞中而非神经元中删除雌激素受体β（ERβ），会诱导出相同的大脑效应。从中年雌性星形胶质细胞-ERβ条件性敲除（cKO）小鼠的海马星形胶质细胞中进行的 RNA 测序和基因表达途径分析显示，糖异生 I 和糖酵解 I 是表达差异最大的途径。烯醇化酶 1 基因的表达在中年雌性星形胶质细胞-ERβ cKO 小鼠的海马体中和绝经后女性的海马体中均增加。功能获得研究表明，ERβ 配体治疗中年雌性小鼠可逆转背侧海马神经病理学。
