Hecheng Wang

Xylocoside G Reduces Amyloid-β Induced Neurotoxicity by Inhibiting NF-κB Signaling Pathway in Neuronal Cells

Amyloid-β (Aβ) peptide, which can invoke a cascade of inflammatory responses, is considered to play a causal role in the development and progress of Alzheimers disease (AD). Xylocoside G (XG) is an active compound isolated from a traditional Chinese medicinal plant, Itoa orientalis. We have previously reported that XG has neuroprotective effects, of which the mechanism is yet unknown. In this study, we investigated the possible mechanisms underlying neuroprotection of XG against Aβ-induced toxicity in SH-SY5Y cells and primary neurons. Pretreatment with XG significantly attenuated the cell viability reduction induced by Aβ exposure in a dose dependent manner which was testified by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase release assay. In addition, pretreatment with XG countered the effect of Aβ on Bax and Bcl-2 expression and repressed Aβ-induced caspase-3 activation, suggesting that the neuroprotective effect of XG is associated with apoptosis regulation. Neuroinflammation has been implicated in Aβ-induced neuronal death. XG significantly attenuated Aβ-stimulated release of inflammatory factors such as tumor necrosis factor-α, interleukin-1β, and prostaglandin E2. It also downregulated the expression of cyclooxygenase-2 in SH-SY5Y cells. Further molecular mechanism studies demonstrated that XG inhibited Aβ-induced NF-κB p65 translocation, which was probably the result of inhibition of JNK phosphorylation but not ERK or p38 MAPK pathway by XG. This is the first study to demonstrate that XG protects SH-SY5Y cells against Aβ-induced inflammation and apoptosis by down-regulating NF-κB signaling pathways.

Surgical Stress Induces Brain‐Derived Neurotrophic Factor Reduction and Postoperative Cognitive Dysfunction Via Glucocorticoid Receptor Phosphorylation in Aged Mice

This study explored whether surgical stress‐induced glucocorticoid receptor (GR) phosphorylation is related to postoperative cognitive dysfunction (POCD) in aged individuals. Inhibition of GR activation could be an effective treatment for POCD.

Long-term effects of neonatal exposure to MK-801 on recognition memory and excitatory–inhibitory balance in rat hippocampus

Blockade of the N-methyl-d-aspartate receptors (NMDARs) during the neonatal period has been reported to induce long-term behavioral and neurochemical alterations that are relevant to schizophrenia. In this study, we examined the effects of such treatment on recognition memory and hippocampal excitatory and inhibitory (E/I) balance in both adolescence and adulthood. After exposure to the NMDAR antagonist, MK-801, at postnatal days (PND) 5-14, male Sprague-Dawley rats were tested for object and object-in-context recognition memory during adolescence (PND 35) and adulthood (PND 63). The parvalbumin-positive (PV+) γ-aminobutyric acid (GABA)-ergic interneurons and presynaptic markers for excitatory and inhibitory neurons, vesicular glutamate transporter-1 (VGLUT1) and vesicular GABA transporter (VGAT) were examined in the hippocampus to reflect the E/I balance. We found that rats receiving MK-801 treatment showed deficits of recognition memory, reduction in PV+ cell counts and upregulation of the VGLUT1/VGAT ratio in both adolescence and adulthood. Notably, the changes of the VGLUT1/VGAT ratio at the two time points exhibited distinct mechanisms. These results parallel findings of hippocampal abnormalities in schizophrenia and lend support to the usefulness of neonatal NMDAR blockade as a potential neurodevelopmental model for the disease.

Histone deacetylase inhibition leads to neuroprotection through regulation on glial function

Background Epigenetic mechanisms such as post-translational histone acetylation are increasingly recognized for their contribution to gene activation and silencing in the brain and contribute to neurodegeneration. Acetylation degree of histones is highly regulated by the enzymes known as histone acetyltransferases (HATs) or histone deacetylases (HDACs). HDAC inhibition affects the expression of only a small subset of genes, leading to transcriptional activation or repression through hyperacetylation of histone or non-histone proteins. HDAC inhibitors are a class of compounds that interfere with the function of HDAC and have been viewed as promising agents to combat neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Multiple mechanisms underlying the effects of HDAC inhibitors on neuroprotection and restoration of memory and motor impairments in AD or PD models have been proposed, however, little is known about the contribution of HDAC inhibition in glial cells. It has been reported that valproic acid (VPA), a drug commonly used for epilepsy and bipolar disorders, upregulates the expression of neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in astrocytes, which contributes to VPAmediated neurotrophic effect on dopamine neurons. VPA also induces microglia apoptosis and suppresses the production of proinflammatory factors in microglia. As VPA is a HDAC inhibitor, we hypothesize that HDAC inhibition may contribute to neuroprotection through regulating gene expressions in glial cells. Materials and methods We thus investigated the effects of several HDAC inhibitors including VPA, trichostatin (TSA), sodium phenylbutyrate (4-PBA) and nicotinamide, on neurotrophic and proinflammatory functions of astrocytes and microglia.

Hypoxia-inducible factor-1α mediates up-regulation of neprilysin by histone deacetylase-1 under hypoxia condition in neuroblastoma cells.

Hypoxia‐inducible factor (HIF)‐1 is the key transcriptional activator mediating both adaptive and pathological responses to hypoxia. The purpose of this study was to find the role of HIF‐1 in regulating neprilysin (NEP) at the early stage of hypoxia and explore the underlying mechanism. In this study, we demonstrated that both NEP mRNA and protein levels in neuroblastoma cells were elevated in early stages of hypoxia. Over‐expression of HIF‐1α gene increased NEP mRNA/protein levels, as well as enzyme activity while knockdown of HIF‐1α decreased them. Meanwhile, HIF‐1α was shown to bind to histone deacetylase (HDAC)‐1 and reduced the association of HDAC‐1 with NEP promoter, thus activating NEP gene transcription in a de‐repression way. In summary, our results indicated that hypoxia in the early stages would up‐regulate NEP expression, in which interaction of HIF‐1α and HDAC‐1 may play a role. This study suggested that NEP up‐regulation might be an adaptive response to hypoxia, which was mediated by HIF‐1α binding to HDAC‐1 at the early stage of hypoxia.

High Manganese, A Risk for Alzheimer's Disease: High Manganese Induces Amyloid-β Related Cognitive Impairment

Excess manganese (Mn) in brain can be neurotoxic, implicated in several neurodegenerative disorders such as sporadic Alzheimers disease (AD). However, little is known about the altered metal environment including elevated Mn in the progressive cognitive impairment of AD. Indeed, whether high Mn is associated with AD risk remains elusive. In the study, we recruited 40 Chinese elders with different cognitive statuses and investigated concentrations of Mn in whole blood and plasma amyloid-β (Aβ) peptides. Surprisingly, there were significant correlations of Mn with Mini-Mental State Examination score and Clinical Dementia Rating Scale score. In addition, plasma Aβ peptides increased with elevated Mn. Further studies both in vitro and in vivo demonstrated dose-related neurotoxicity and increase of Aβ by Mn treatment, which was probably caused by disrupted Aβ degradation. These data suggested that high Mn may be involved in the progress of AD as an essential pathogenic factor.

Phospholipid transfer protein (PLTP) deficiency accelerates memory dysfunction through altering amyloid precursor protein (APP) processing in a mouse model of Alzheimer's disease

Phospholipid transfer protein (PLTP) is a widely expressed lipid transfer protein participating in the transport of cholesterol and other lipids in the plasma and peripheral tissues. Recently, elevated amyloid β (Aβ) in young and aged PLTP-deficient brains had been reported. However, the role of PLTP in amyloid precursor protein (APP) processing and Alzheimers disease (AD) pathology remains elusive. Here we first found that deficiency of PLTP accelerated memory dysfunction in APP/PS1ΔE9 AD model mice at the age of 3 months. Further characterization showed that PLTP deficiency increased soluble Aβ peptides, and intracellular accumulation of Aβ was illustrated, which might be due to disrupted APP turnover and the enhanced amyloidogenic pathway. Besides, reduced brain-derived neurotrophic factor (BDNF) was found in PLTP-deficient APP/PS1ΔE9 mice, and the BDNF level was negatively correlated with Aβ42 content, instead of Aβ40 content. In addition, autophagic dysfunction was found in the PLTP-deficient APP/PS1ΔE9 mice. Our data presented a novel model to link phospholipid metabolism to APP processing and also suggested that PLTP played an important role in Aβ metabolism and would be useful to further elucidate functions of PLTP in AD susceptibility.

Impaired synaptic vesicle recycling contributes to presynaptic dysfunction in lipoprotein lipase-deficient mice

Lipoprotein lipase (LPL) is expressed at high levels in hippocampal neurons, although its function is unclear. We previously reported that LPL-deficient mice have learning and memory impairment and fewer synaptic vesicles in hippocampal neurons, but properties of synaptic activity in LPL-deficient neurons remain unexplored. In this study, we found reduced frequency of miniature excitatory postsynaptic currents (mEPSCs) and readily releasable pool (RRP) size in LPL-deficient neurons, which led to presynaptic dysfunction and plasticity impairment without altering postsynaptic activity. We demonstrated that synaptic vesicle recycling, which is known to play an important role in maintaining the RRP size in active synapses, is impaired in LPL-deficient neurons. Moreover, lipid assay revealed deficient docosahexaenoic acid (DHA) and arachidonic acid (AA) in the hippocampus of LPL-deficient mice; exogenous DHA or AA supplement partially restored synaptic vesicle recycling capability. These results suggest that impaired synaptic vesicle recycling results from deficient DHA and AA and contributes to the presynaptic dysfunction and plasticity impairment in LPL-deficient neurons.

The dishomeostasis of metal ions plays an important role for the cognitive impartment

Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer’s disease (AD) and might underlie memory impairment. The homeostasis of metal ions plays an important role in health and neurodegenerative disease by influencing cellular biochemical pathways. The disturbance of some metal ions may have cytotoxic effects, which may cause cell death leading to neurodegenerative disorders such as AD. The aim of the present study was to investigate metal concentrations in whole blood from Chinese AD patients with APOE e4 allele carrier. Concentrations of metals (magnesium, calcium, manganese, iron, cobalt, copper, zinc, selenium, cadmium, mercury and lead) were determined in whole blood by inductively coupled plasma mass spectrometry (ICP-MS) in 40 Chinese people with different Mini-mental state examination (MMSE) score. Normal APP processing could be restored when magnesium was adjusted back to physiological concentration. Our findings suggest that supplementation of magnesium has a therapeutic potential for preventing AD. We observed that Plasma Mg, Zn and Se levels were found to be significantly lower in patients with AD compared with controls. Furthermore, there is a significant negative correlation between manganese and MMSE score. Whereas other metal ions have no association with MMSE score. These result suggests that dishomeostasis of metal ions may involve in the progress of AD pathology, and elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of AD and may have therapeutic potential for treating AD in humans.

Testosterone regulates Arp2/3 expression by DNA methylation in hippocampus

Background The Arp2/3 complex is a seven-protein assembly that is critical for actin nucleation and branching in cells. Although some DNA methylation patterns are altered by steroid hormone exposure in the developing brain, less is known about how changes in steroid hormone levels influence Arp2/3 complex DNA methylation patterns in the adult brain. Steroid hormones act in the adult brain to regulate gene expression. Specifically, the expression of the Arp2 within adult brain is dependent upon testosterone exposure.