Shao Li

Scorpion venom heat-resistant peptide (SVHRP) enhances neurogenesis and neurite outgrowth of immature neurons in adult mice by up-regulating brain-derived neurotrophic factor (BDNF).

Scorpion venom heat-resistant peptide (SVHRP) is a component purified from Buthus martensii Karsch scorpion venom. Although scorpions and their venom have been used in Traditional Chinese Medicine (TCM) to treat chronic neurological disorders, the underlying mechanisms of these treatments remain unknown. We applied SVHRP in vitro and in vivo to understand its effects on the neurogenesis and maturation of adult immature neurons and explore associated molecular mechanisms. SVHRP administration increased the number of 5-bromo-2’-dexoxyuridine (BrdU)-positive cells, BrdU- positive/neuron-specific nuclear protein (NeuN)-positive neurons, and polysialylated-neural cell adhesion molecule (PSA-NCAM)-positive immature neurons in the subventricular zone (SVZ) and subgranular zone (SGZ) of hippocampus. Furthermore immature neurons incubated with SVHRP-pretreated astrocyte-conditioned medium exhibited significantly increased neurite length compared with those incubated with normal astrocyte-conditioned medium. This neurotrophic effect was further confirmed in vivo by detecting an increased average single area and whole area of immature neurons in the SGZ, SVZ and olfactory bulb (OB) in the adult mouse brain. In contrast to normal astrocyte-conditioned medium, higher concentrations of brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF) was detected in the conditioned medium of SVHRP-pretreated astrocytes, and blocking BDNF using anti-BDNF antibodies eliminated these SVHRP-dependent neurotrophic effects. In SVHRP treated mouse brain, more glial fibrillary acidic protein (GFAP)-positive cells were detected. Furthermore, immunohistochemistry revealed increased numbers of GFAP/BDNF double-positive cells, which agrees with the observed changes in the culture system. This paper describes novel effects of scorpion venom-originated peptide on the stem cells and suggests the potential therapeutic values of SVHRP.

Update on the Neuroprotective Effect of Estrogen Receptor Alpha Against Alzheimer's Disease

Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and disordered cognition. Women have a higher AD incidence than men, indicating that the declining estrogen levels during menopause may influence AD pathogenesis. However, the mechanism underlying estrogens neuroprotective effect is not fully clarified and is complicated by the presence of several distinct estrogen receptor (ER) types and the identification of a growing number of ER splice variants. Thus, a deeper analysis of ERs could elucidate the role of estrogen in age-related cognitive changes. Intracellular calcium signaling cascades play a pivotal role in ERα neuroprotection against AD. The ERα-mediated inhibition of Death domain-associated protein (Daxx) translocation and the combination of membrane ERα and caveolin in caveolae may protect against AD. Moreover, the voltage-dependent anion channel (VDAC)/ERα association may be important for maintaining channel inactivation and may be relevant in neuronal preservation against Aβ injury. Additionally, ERα may prevent glutamate excitotoxic injury by Aβ through estrogen signaling mechanisms. ERα and IGF-IR co-activation may mediate neuroprotection, and many other growth factors and intracellular signaling responses triggered by ERα may also play important roles in this process. Furthermore, details regarding the genes and mRNA variants of ERα that are expressed in different parts of the human organs have been clarified recently. Therefore, here we review the literature to clarify the neuroprotective role of ERα. This review focuses on the potential mechanisms mediated by ERα in the intracellular signaling events in nervous system cells, thereby clarifying ERα-mediated protection against AD.

Dysregulation of synaptic and extrasynaptic N-methyl-D-aspartate receptors induced by amyloid-β

The toxicity of amyloid-beta (Aβ) is strongly associated with Alzheimer’s disease (AD), which has a high incidence in the elderly worldwide. Recent evidence showed that alteration in the activity of N-methyl-D-aspartate receptors (NMDARs) plays a key role in Aβ-induced neurotoxicity. However, the activation of synaptic and extrasynaptic NMDARs has distinct consequences for plasticity, gene regulation, neuronal death, and Aβ production. This review focuses on the dysregulation of synaptic and extrasynaptic NMDARs induced by Aβ. On one hand, Aβ downregulates the synaptic NMDAR response by promoting NMDAR endocytosis, leading to either neurotoxicity or neuroprotection. On the other hand, Aβ enhances the activation of extrasynaptic NMDARs by decreasing neuronal glutamate uptake and inducing glutamate spillover, subsequently causing neurotoxicity. In addition, selective enhancement of synaptic activity by low doses of NMDA, or reduction of extrasynaptic activity by memantine, a non-competitive NMDAR antagonist, halts Aβ-induced neurotoxicity. Therefore, future neuroprotective drugs for AD should aim at both the enhancement of synaptic activity and the disruption of extrasynaptic NMDAR-dependent death signaling.

Lamotrigine Attenuates Deficits in Synaptic Plasticity and Accumulation of Amyloid Plaques in APP/PS1 Transgenic Mice

Hyperactivity and its compensatory mechanisms may causally contribute to synaptic and cognitive deficits in Alzheimers disease (AD). Blocking the overexcitation of the neural network, with levetiracetam (LEV), a sodium channel blocker applied in the treatment of epilepsy, prevented synaptic and cognitive deficits in human amyloid precursor protein (APP) transgenic mice. This study has brought the potential use of antiepileptic drugs (AEDs) in AD therapy. We showed that the chronic treatment with lamotrigine (LTG), a broad-spectrum AED, suppressed abnormal spike activity, prevented the loss of spines, synaptophysin immunoreactivity, and neurons, and thus attenuated the deficits in synaptic plasticity and learning and memory in APP and presenilin 1 (PS1) mice, which express human mutant APP and PS1. In contrast with LEV, which failed to reduce the generation of amyloid β, the chronic LTG treatment reduced the cleavage of APP by β-secretase and thus the numbers and the size of amyloid plaques in the brains of APP and PS1 mice. Moreover, the levels of brain-derived neurotrophic growth factor (BDNF) and nerve growth factor (NGF) were enhanced in the brains of APP and PS1 mice by the chronic LTG treatment. Therefore, these observations demonstrate that LTG attenuates AD pathology through multiple mechanisms, including modulation of abnormal network activity, reduction of the generation of amyloid beta and upregulation of BDNF and NGF.

Estrogen receptors’ neuroprotective effect against glutamate-induced neurotoxicity

Glutamate is the most abundant excitatory brain neurotransmitter that has important functional significance with respect to neurodegenerative conditions. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease (AD) has been gradually becoming elucidated recently. Excessive release of glutamate induces an increase in intracellular Ca2+ levels, thus triggers a cascade of cellular responses, ultimately leading to neuronal cell death. This type of neuronal damage induced by over-excitation has been proposed to be involved in a number of neuropathological conditions, ranging from acute insults to chronic neurodegenerative disorders. Estrogen could be effective in modulating glutamate-induced neurotoxicity and the protective responsivenesses are mostly estrogen receptors (ERs)-dependent. However, the mechanism underlying estrogen’s neuroprotective effect is not fully clarified and is complicated by the presence of several distinct ER types. So a deeper research into the neuroprotection of ERs might be informative about the positive effect that estrogen might have on ageing-related cognitive changes. Extensive studies have indicated the neuroprotective effects of ERs against glutamate-induced neurotoxicity. The purpose of this review is to elucidate ERs’ neuroprotective effects against glutamate-induced cytotoxicity and explore new ways to prevent and cure neurotoxicity-associated neurodegenerative disorders.

Potential Roles of Exosomal MicroRNAs as Diagnostic Biomarkers and Therapeutic Application in Alzheimer’s Disease

Exosomes are bilipid layer-enclosed vesicles derived from endosomes and are released from neural cells. They contain a diversity of proteins, mRNAs, and microRNAs (miRNAs) that are delivered to neighboring cells and/or are transported to distant sites. miRNAs released from exosomes appear to be associated with multiple neurodegenerative conditions linking to Alzheimers disease (AD) which is marked by hyperphosphorylated tau proteins and accumulation of Aβ plaques. Exciting findings reveal that miRNAs released from exosomes modulate the expression and function of amyloid precursor proteins (APP) and tau proteins. These open up the possibility that dysfunctional exosomal miRNAs may influence AD progression. In addition, it has been confirmed that the interaction between miRNAs released by exosomes and Toll-like receptors (TLR) initiates inflammation. In exosome support-deprived neurons, exosomal miRNAs may regulate neuroplasticity to relieve neurological damage. In this review, we summarize the literature on the function of exosomal miRNAs in AD pathology, the potential of these miRNAs as diagnostic biomarkers in AD, and the use of exosomes in the delivery of miRNAs which may lead to major advances in the field of macromolecular drug delivery.

Microbial lipid production by oleaginous yeast in D-xylose solution using a two-stage culture mode

The economical production of biodiesel from lignocellulose hydrolysates requires a robust D-xylose fermentation path. The present work found that Lipomyces starkeyi AS 2.1560 and Rhodosporidium toruloides AS 2.1389 could produce micro-lipid effectively from D-xylose solution by a two-stage culture mode. Results demonstrated that both L. starkeyi and R. toruloides could achieve high lipid production in xylose solution. High cell density fermentation was carried out by a feed-batch fermentation mode. After fermentation for 48 h in a bioreactor using unsterile xylose solution by L. starkeyi, the biomass, lipid and lipid content reached 97.4 g L−1, 63.9 g L−1, and 65.5%, respectively. Accordingly, the lipid productivity reached 1.3 g L−1 h−1 in the second stage. And the overall lipid productivity was 0.55 g L−1 h−1. Therefore, L. starkeyi and R. toruloides are highly effective D-xylose-fermenting oleaginous yeasts for lipid production in xylose solution. The two-stage culture method should provide a new opportunity to make the industrial production of biodiesel possible in the future.

Roles of NG2 glial cells in diseases of the central nervous system

NG2 cells are a novel distinct class of central nervous system (CNS) glial cells, characterized by the expression of the chondroitin sulfate proteoglycan NG2. They have been detected in a variety of human CNS diseases. As morphological, physiological and biomolecular studies of NG2 cells have been conducted, their roles have been gradually revealed. Research on cellular and molecular mechanisms in the pathophysiological state was built on the preliminary findings of their physiological functions; and in turn, this helps to clarify their physiological roles and leads to the identification of novel therapeutic targets. This review summarizes recent findings regarding the potential roles of NG2 cells in traumatic brain injury, multiple sclerosis, glioma, epilepsy, Alzheimer’s disease and electroconvulsive therapy for depression.摘要NG2细胞是新发现的一类广泛存在于成熟和发育期中枢神经系统的胶质细胞群体。这些细胞表面表达NG2 硫酸软骨素蛋白多糖, 因而常被称作NG2细胞。随着NG2细胞形态学研究的深入, NG2胶质细胞的功能也越来越受到关注。NG2细胞在人类多种中枢神经系统疾病中扮演重要角色。本文结合最新的研究报道, 就其在一些常见的中枢神经系统疾病中的作用进行概括综述。NG2 cells are a novel distinct class of central nervous system (CNS) glial cells, characterized by the expression of the chondroitin sulfate proteoglycan NG2. They have been detected in a variety of human CNS diseases. As morphological, physiological and biomolecular studies of NG2 cells have been conducted, their roles have been gradually revealed. Research on cellular and molecular mechanisms in the pathophysiological state was built on the preliminary findings of their physiological functions; and in turn, this helps to clarify their physiological roles and leads to the identification of novel therapeutic targets. This review summarizes recent findings regarding the potential roles of NG2 cells in traumatic brain injury, multiple sclerosis, glioma, epilepsy, Alzheimer’s disease and electroconvulsive therapy for depression. NG2细胞是新发现的一类广泛存在于成熟和发育期中枢神经系统的胶质细胞群体。这些细胞表面表达NG2 硫酸软骨素蛋白多糖, 因而常被称作NG2细胞。随着NG2细胞形态学研究的深入, NG2胶质细胞的功能也越来越受到关注。NG2细胞在人类多种中枢神经系统疾病中扮演重要角色。本文结合最新的研究报道, 就其在一些常见的中枢神经系统疾病中的作用进行概括综述。

Elevated Neuronal Excitability Due to Modulation of the Voltage-Gated Sodium Channel Nav1.6 by Aβ1−42

Aberrant increases in neuronal network excitability may contribute to the cognitive deficits in Alzheimers disease (AD). However, the mechanisms underlying hyperexcitability are not fully understood. Such overexcitation of neuronal networks has been detected in the brains of APP/PS1 mice. In the present study, using current-clamp recording techniques, we observed that 12 days in vitro (DIV) primary cultured pyramidal neurons from P0 APP/PS1 mice exhibited a more prominent action potential burst and a lower threshold than WT littermates. Moreover, after treatment with Aβ1−42 peptide, 12 DIV primary cultured neurons showed similar changes, to a greater degree than in controls. Voltage-clamp recordings revealed that the voltage-dependent sodium current density of neurons incubated with Aβ1−42 was significantly increased, without change in the voltage-dependent sodium channel kinetic characteristics. Immunohistochemistry and western blot results showed that, after treatment with Aβ1−42, expressions of Nav and Nav1.6 subtype increased in cultured neurons or APP/PS1 brains compared to control groups. The intrinsic neuronal hyperexcitability of APP/PS1 mice might thus be due to an increased expression of voltage-dependent sodium channels induced by Aβ1−42. These results may illuminate the mechanism of aberrant neuronal networks in AD.

Amyloid precursor protein at node of Ranvier modulates nodal formation.

Amyloid precursor protein (APP), commonly associated with Alzheimer disease, is upregulated and distributes evenly along the injured axons, and therefore, also known as a marker of demyelinating axonal injury and axonal degeneration. However, the physiological distribution and function of APP along myelinated axons was unknown. We report that APP aggregates at nodes of Ranvier (NOR) in the myelinated central nervous system (CNS) axons but not in the peripheral nervous system (PNS). At CNS NORs, APP expression co-localizes with tenascin-R and is flanked by juxtaparanodal potassium channel expression demonstrating that APP localized to NOR. In APP-knockout (KO) mice, nodal length is significantly increased, while sodium channels are still clustered at NORs. Moreover, APP KO and APP-overexpressing transgenic (APP TG) mice exhibited a decreased and an increased thickness of myelin in spinal cords, respectively, although the changes are limited in comparison to their littermate WT mice. The thickness of myelin in APP KO sciatic nerve also increased in comparison to that in WT mice. Our observations indicate that APP acts as a novel component at CNS NORs, modulating nodal formation and has minor effects in promoting myelination.