Fig. 8: ERβ ligand treatment reverses dorsal hippocampal pathology in female mice at midlife.

a Schematic showing timing of gonadectomy (GDX) or sham (Sham) surgery, ERβ ligand (ERβ L) or vehicle (V) treatment, MWM cognitive assessment, and neuropathology (PATH). b Gonadally intact vehicle-treated midlife females (Sham + V, solid), gonadectomized vehicle-treated midlife females (GDX + V, diagonal lines) or gonadectomized ERβ ligand-treated midlife females (GDX + ERβ L, crossed lines) were assessed for spatial reference memory by MWM. Gonadally intact vehicle-treated mice showed preference for the TQ over the OQ (p < 0.0001), while gonadectomized vehicle-treated did not. In contrast, gonadectomized ERβ ligand-treated showed preference for the TQ over the OQ (p = 0.007). Blue line indicates the null hypothesis (25% in TQ). Sham + V, n = 10; GDX + V, n = 6; GDX + ERβ L, n = 7. Quantitative analysis of (c) LCN2⁺GFAP⁺ area fraction for astrocyte reactivity, (d) MHCII⁺IBA1⁺ area fraction for activated microglia, (e) CLEC7A⁺P2RY12⁺ area fraction for disease-associated microglia (DAM), and (f) SYN1⁺PSD95⁺ area fraction for synaptic loss, each in dorsal hippocampus CA1 region in sham + V (solid), GDX + V (diagonal lines), and GDX + ERβ L (crossed lines). GDX + V showed increased reactive astrocytes (p < 0.0001), activated microglia (p = 0.0003), and disease-associated microglia (DAM) (p = 0.0027), as well as synaptic loss (p = 0.0034), each as compared to the Sham + V group. In contrast, there was a decrease in reactive astrocytes (p = 0.0046), activated microglia (p = 0.0007), and disease-associated microglia (DAM) (p = 0.0346), with increased synaptic staining (p = 0.0445) in GDX + ERβ L treated compared to GDX + V treated. Sham + V, n = 8; GDX + V, n = 14; GDX + ERβ L, n = 4. Two-sided Mann–Whitney U test. Box plots with center lines showing the medians, boxes indicating the interquartile range, and whiskers indicating from the minimum and to the maximum values.