Evidence of altered depression and dementia‐related proteins in the brains of young rats after ovariectomy

Abstract

Menopause, a risk factor for brain dysfunction in women, is characterized by neuropsychological symptoms including depression and dementia, which are closely related to alterations in different brain regions after menopause. However, little is known about the variability in pathophysiologic changes associated with menopause in the brain. Here, we observed that menopause in rats induced by bilateral ovariectomy (OVX) showed depressive and dementia-related behaviors along with neuronal loss in the prefrontal cortex (PFC), hippocampus (HIP), hypothalamus (HYP), and amygdala (AMY) by Nissl staining. Meanwhile, by immunohistochemical staining, increased microglia in the HIP and AMY and increased astrocytes in the PFC, HYP, and AMY were shown. Using quantitative proteomics, we identified 146 differentially expressed proteins in the brains of OVX rats, for example, 20 in the PFC, 41 in the HIP, 17 in the HYP, and 79 in the AMY, and performed further detection by western blotting. A link between neuronal loss and apoptosis was suggested, as evidenced by increases in adenylate kinase 2 (AK2), B-cell lymphoma 2 associated X (Bax), cleaved caspase 3, and phosphorylated p53 and decreases in Huntingtin-interacting protein K, hexokinase, and phosphorylated B-cell lymphoma 2 (Bcl-2), and apoptosis might be triggered by endoplasmic reticulum stress (probed by increased glucose-regulated protein 78 (GRP78), cleaved caspase 12, phosphorylated protein kinase R (PKR)-like endoplasmic reticulum kinase, inositol-requiring enzyme-1 and activating transcription factor 6), and mitochondrial dysfunction (probed by increased cytochrome c and cleaved caspase 3 and decreased sideroflexin-1 (SFXN1) and NADH dehydrogenase (ubiquinone) 1 α subcomplex 11 (NDUFA11)). Activation of autophagy was also indicated by increased autophagy-related 7, γ-aminobutyric acid (GABA) receptor-associated protein-like 2, and oxysterol-binding protein-related protein 1 and confirmed by increased microtubule-associated protein light chain 3 (LC3II/I), autophagy-related 5, and Beclin1 in the HIP and AMY. In the AMY, which is important in emotion, higher GABA transporter 3 and lower vesicular glutamate transporter 1 levels indicated an imbalance between excitatory and inhibitory neurotransmission, and the increased calretinin and decreased calbindin levels suggested an adjustment of GABAergic transmission after OVX. In addition, cytoskeletal abnormalities including tau hyperphosphorylation, dysregulated Ca² signals, and glutamic synaptic impairments were observed in the brains of OVX rats. Collectively, our study showed the changes in different brain regions related to depression and dementia during menopause.

Adolescent stress increases depression-like behaviors and alters the excitatory-inhibitory balance in aged mice

“…While the basolateral amygdala is a more cortical-like structure, [41] the central amygdala is heavily populated by GABAergic medium spiny neurons. [42] Recent studies have reported increased depression-like behaviors and elevated CR expression levels in the amygdala of mice subjected to maternal separation or bilateral ovariectomy, [43,44] providing a link between depressive behaviors and amygdala CR levels.…”

Emodin Prevented Depression in Chronic Unpredicted Mild Stress Exposured Rats by Targeting MiR139-5p/5-Lipoxygenase

“…The hippocampal proteomic analysis was conducted as previously described [21,22,24]. Brie y, the hippocampal proteins were extracted, digested and labeled by iTRAQ-6plex reagents in accordance with the manufacturer's protocol.…”

Estrogen deficiency induces memory loss via altered hippocampal HB-EGF and autophagy

“…Likewise, autophagy contributed to the estradiol-mediated protective effect on endotoxemiainduced multiple organ dysfunction (Chung et al 2017), overall indicating a cell type specific effect of estrogen deficiency on autophagy. In terms of the brain, there have been two in vivo reports, one demonstrating a shortand long-term ovarian hormone-dependent differential response on autophagy in the cortex-hippocampus mixture (Yao et al 2018), and the other claiming increased hippocampal autophagy following OVX (Fang et al 2018), marked by altered p62, Beclin-1, ATG5 and LC3-II protein levels. However, unlike ours, the studies did not delve into the autophagy regulation mechanism particularly in the hippocampal neurons.…”

“…The primary female sex hormone, estrogen, activates its receptors, ERα and ERβ, and exhibits physiological functions within the brain (Mukai et al 2010, Hara et al 2015. Correspondingly, ovarian failure and estrogen deficiency, which characterize menopause in women, suppress cerebral ER levels (Qu et al 2013, Fang et al 2018 and alter neuronal functions, including cognition (Kim et al 2016, Djiogue et al 2018. Estrogen deficiency induces hippocampal apoptosis, neuronal loss (Sales et al 2010, Yazgan & Naziroglu 2017 and cognitive dysfunctions (Kim et al 2016, Djiogue et al 2018, while estradiol therapy reduces apoptosis and improves learning-memory performances (Sales et al 2010, Uzum et al 2016, Yazgan & Naziroglu 2017.…”