p38 and ERK1/2-Dependent Activation of c-Jun Is Required for the Downregulation of Oxidative Stress-Induced ERα in Hypothalamic Astrocytes.

INTRODUCTION: Gonadotropin-releasing hormone (GnRH) is a hypothalamic neuropeptide that plays important roles in the female fertility. Accumulating evidence suggests that ERα present in the astrocytes of the hypothalamus region is essential for production of GnRH. The astrocytes display age-related senescence associated to oxidative stress induced by the estrogen metabolites. However, it is still unclear whether and how ERα expression changes during astrocyte aging. METHODS: Immunofluorescence was performed to analyze the ERα gene levels in hypothalamic astrocytes of naturally aging C57BL/6J female mice. We employed an oxidative stress cell model receiving 2-hydroxyestradiol (2OH-E2) intervention to confirm the downregulation of ERα expression in primary astrocytes. Western blot analysis was used to explore which oxidative stress signaling pathways induced loss of the ERα gene. Finally, ChIP-qPCR was employed to evaluate whether the c-Jun protein is able to regulate ERα gene expression. RESULTS: Compared to young mice, we found that the ERα expression of mid-aged mice was significantly decreased. In hypothalamic astrocytes, 2OH-E2 treatment significantly reduced the expression of the ERα gene. Moreover, we observed that transcription factor c-Jun could directly inhibit transcriptional ERα gene expression and might also reduce it by decreasing H3K27 acetylation at promoter regions. Administration of the antioxidants Rg1 and astaxanthin significantly attenuated the decrease in ERα gene expression induced by oxidative stress. CONCLUSIONS: The current data demonstrate that oxidative stress leads to loss of ERα involving the activation of the p38 and ERK1/2 pathways and the induction of the c-Jun protein in hypothalamic astrocytes. C-Jun protein regulates ERα gene expression via direct transcriptional repression or involving histone acetylation modifications at ERα gene promoter sites.

APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline.

Population-based studies reveal that apolipoprotein E (APOE) ε4 gene allele is closely associated with late-life depression (LLD). However, its exact role and underlying mechanism remain obscure. The current study found that aged apoE4-targeted replacement (TR) mice displayed obvious depression-like behavior when compared with age-matched apoE3-TR mice. Furthermore, apoE4 increased stress-induced depression-like behaviors, accompanied by declines in the hippocampal 5-HT (1A) radioligand [18F] MPPF uptake evidenced by positron emission tomography (PET). In [18F]-fluorodeoxyglucose PET ([18F]-FDG PET) analyses, the FDG uptake in the prefrontal cortex, temporal cortex and hippocampus of apoE4-TR mice significantly declined when compared with that of apoE3-TR mice after acute stress. Further biochemical analysis revealed that ATP levels in the prefrontal cortex of apoE4-TR mice decreased during aging or stress process and ATP supplementation effectively rescued the depression-like behaviors of elderly apoE4-TR mice. In primary cultured astrocytes from the cortex of apoE-TR mice, apoE4, when compared with apoE3, obviously decreased the mitochondrial membrane potential, mitochondrial respiration, and glycolysis in a culture time-dependent manner. Our findings highlight that apoE4 is a potential risk factor of depression in elderly population by impairing the glucose metabolism, reducing ATP level, and damaging mitochondrial functions in astrocytes, which indicates that in clinical settings ATP supplementation may be effective for elderly depression patients with apoE4 carrier.

Acetate supplementation produces antidepressant-like effect via enhanced histone acetylation.

BACKGROUND: Abnormal energy metabolism is often documented in the brain of patients and rodents with depression. In metabolic stress, acetate serves as an important source of acetyl coenzyme A (Ac-CoA). However, its exact role and underlying mechanism remain to be investigated. METHOD: We used chronic social failure stress (CSDS) to induce depression-like phenotype of C57BL/6J mice. The drugs were administered by gavage. We evaluated the depressive symptoms by sucrose preference test, social interaction, tail suspension test and forced swimming test. The dendritic branches and spine density were detected by Golgi staining, mRNA level was analyzed by real-time quantitative RT-PCR, protein expression level was detected by western blot, and the content of Ac-CoA was detected by ELISA kit. RESULT: The present study found that acetate supplementation significantly improved the depression-like behaviors of mice either in acute forced swimming test (FST) or in CSDS model and that acetate administration enhanced the dendritic branches and spine density of the CA1 pyramidal neurons. Moreover, the down-regulated levels of BDNF and TrkB were rescued in the acetate-treated mice. Of note, chronic acetate treatment obviously lowered the transcription level of HDAC2, HDAC5, HDAC7, HDAC8, increased the transcription level of HAT and P300, and boosted the content of Ac-CoA in the nucleus, which facilitated the acetylation levels of histone H3 and H4. LIMITATIONS: The effect of acetate supplementation on other brain regions is not further elucidated. CONCLUSION: These findings indicate that acetate supplementation can produce antidepressant-like effects by increasing histone acetylation and improving synaptic plasticity in hippocampus.

Estradiol-induced senescence of hypothalamic astrocytes contributes to aging-related reproductive function declines in female mice.

Hypothalamic astrocytes are important contributors that activate gonadotropin-releasing hormone (GnRH) neurons and promote GnRH/LH (luteinizing hormone) surge. However, the potential roles and mechanisms of astrocytes during the early reproductive decline remain obscure. The current study reported that, in intact middle-aged female mice, astrocytes within the hypothalamic RP3V accumulated senescence-related markers with increasing age. It employed an ovariectomized animal model and a cell model receiving estrogen intervention to confirm the estrogen-induced senescence of hypothalamic astrocytes. It found that estrogen metabolites may be an important factor for the estrogen-induced astrocyte senescence. In vitro molecular analysis revealed that ovarian estradiol activated PKA and up-regulated CYPs expression, metabolizing estradiol into 2-OHE2 and 4-OHE2. Of note, in middle-aged mice, the progesterone synthesis and the ability to promote GnRH release were significantly reduced. Besides, the expression of growth factors decreased and the mRNA levels of proinflammatory cytokines significantly increased in the aging astrocytes. The findings confirm that ovarian estradiol induces the senescence of hypothalamic astrocytes and that the senescent astrocytes compromise the regulation of progesterone synthesis and GnRH secretion, which may contribute to the aging-related declines in female reproductive function.

Curcumin Ameliorates Memory Decline via Inhibiting BACE1 Expression and ß-Amyloid Pathology in 5×FAD Transgenic Mice.

Alzheimer's disease (AD) is the most common dementia and the trigger of its pathological cascade is widely believed to be the overproduction and accumulation of ß-amyloid protein (Aß) in the affected brain. However, effective AD remedies are still anxiously awaited. Recent evidence suggests that curcumin may be a potential agent for AD treatment. In this study, we used 5×FAD transgenic mice as an AD model to investigate the effects of curcumin on AD. Our results showed that curcumin administration (150 or 300 mg/kg/day, intragastrically, for 60 days) dramatically reduced Aß production by downregulating BACE1 expression, preventing synaptic degradation, and improving spatial learning and memory impairment of 5×FAD mice. These findings suggest that curcumin is a potential candidate for AD treatment.

Tripchlorolide improves cognitive deficits by reducing amyloid ß and upregulating synapse-related proteins in a transgenic model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by early impairments in memory and progressive neurodegeneration. Disruption of synaptic plasticity processes that underlie learning and memory contribute partly to this pathophysiology. Tripchlorolide (T4 ), an extract from a traditional Chinese herbal Tripterygium wilfordii Hook F, has been shown to be neuroprotective in animal models of Parkinson's disease and to improve cognitive deficits in senescence-accelerated mouse P8. In this study, we investigated the effect of T4 on cognitive decline and synaptic plasticity in five times familial AD (5XFAD) mice co-expressing mutated amyloid precursor protein and presenilin-1. Five-month-old 5XFAD mice and wild type littermates were intraperitoneally injected with T4 , 5 µg/kg or 25 µg/kg, every other day for 60 days. T4 treatment significantly improved spatial learning and memory, alleviated synaptic ultrastructure degradation, up-regulated expression of synapse-related proteins, including synaptophysin, post-synaptic density-95, N-methyl-D-aspartate receptor subunit 1, phosphorylation of calcium/calmodulin dependent protein kinase II α, and phosphorylation of cyclic AMP-response element binding protein, and promoted activation of the phophoinositide-3-kinase-Akt-mammalian target of rapamycin signaling pathway in 5XFAD mice. Accumulation of amyloid ß (Aß) may contribute to synapse dysfunction and memory impairment in AD. We found that T4 treatment significantly reduced cerebral Aß deposits and lowered Aß levels in brain homogenates. These effects coincided with a reduction in cleavage of ß-carboxyl-terminal amyloid precursor protein (APP) fragment, levels of soluble APPß, and protein expression of ß-site APP cleaving enzyme 1. Taken together, our findings identify T4 as a potent negative regulator of brain Aß levels and show that it significantly ameliorates synaptic degeneration and cognitive deficits in a mouse model of AD.