Dihydroartemisinin promotes tau O-GlcNAcylation and improves cognitive function in hTau transgenic mice.

Tauopathy is a collective term for several neurodegenerative diseases characterized by the intracellular accumulation of hyperphosphorylated microtubule-associated protein Tau (P-tau). Our recent report has revealed the neuroprotective effect of dihydroartemisinin (DHA) on mice overexpressing human Tau (hTau) in the hippocampus by enhancing O-linked-N-Acetylglucosaminylation (O-GlcNAcylation) modification. However, whether DHA can improve synaptic and cognitive function in hTau transgenic mice by specifically promoting Tau O-GlcNAcylation is still unclear. Here, we introduced hTau transgenic mice, a more optimal tauopathy model, to study the effect of DHA on Tau O-GlcNAcylation. We reported that DHA treatment alleviated the deficits of hippocampal CA1 LTP and spatial learning and memory in the Barnes maze and context fear conditioning tests in hTau transgenic mice. Mechanically, we revealed that DHA exerted a significant protective effect by upregulating Tau O-GlcNAcylation and attenuating Tau hyperphosphorylation. Through molecular docking, we found a stable binding between DHA and O-GlcNAc transferase (OGT). We further reported that DHA treatment had no effect on the expression of OGT, but it promoted OGT nuclear export, thereby enhancing OGT-mediated Tau O-GlcNAcylation. Taken together, these results indicate that DHA exerts neuroprotective effect by promoting cytoplasmic translocation of OGT and rebuilding the balance of Tau O-GlcNAcylation/phosphorylation, enhancing O-GlcNAcylation of Tau, suggesting that DHA may be a potential therapeutic agent against tauopathy.

miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1-containing AMPA receptors in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3'-untranslated region (3' UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aß accumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation.

Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a calcium-dependent serine proteinase that regulates the proteolytic activity of various precursor proteins and facilitates protein maturation. Dysregulation of PCSK6 expression or function has been implicated in several pathological processes including nervous system diseases. However, whether and how PCSK6 is involved in the pathogenesis of Alzheimer's disease (AD) remains unclear. In this study, we reported that the expression of PCSK6 was significantly increased in the brain tissues of postmortem AD patients and APP23/PS45 transgenic AD model mice, as well as N2AAPP cells. Genetic knockdown of PCSK6 reduced amyloidogenic processing of APP in N2AAPP cells by suppressing the activation of membrane-type 5-matrix metalloproteinase (MT5-MMP), referred to as η-secretase. We further found that PCSK6 cleaved and activated MT5-MMP by recognizing the RRRNKR sequence in its N-terminal propeptide domain in N2A cells. The mutation or knockout of this cleavage motif prevented PCSK6 from interacting with MT5-MMP and performing cleavage. Importantly, genetic knockdown of PCSK6 with adeno-associated virus (AAV) reduced Aß production and ameliorated hippocampal long-term potentiation (LTP) and long-term spatial learning and memory in APP23/PS45 transgenic mice. Taken together, these results demonstrate that genetic knockdown of PCSK6 effectively alleviate AD-related pathology and cognitive impairments by inactivating MT5-MMP, highlighting its potential as a novel therapeutic target for AD treatment.

7,8-Dihydroxyflavone ameliorates cognitive impairment induced by repeated neonatal sevoflurane exposures in mice through increasing tau O-GlcNAcylation.

BACKGROUND: Sevoflurane, one of the most commonly used general anesthetics for pediatric anesthesia, has recently gained significant attention in both preclinical and clinical settings due to its potential neurotoxicity in the developing brain. Tau phosphorylation, induced by sevoflurane, is recognized as one of the major causes of neurotoxicity. 7,8-dihydroxyflavone (DHF), a TrkB receptor agonist, has been reported to exhibit potential neuroprotective effects against tauopathies. In this study, our objective was to investigate whether DHF could provide neuroprotective effects against sevoflurane-induced neurotoxicity and explore the underlying molecular mechanisms. METHODS: Six-day-old mice were subjected to 2 h of anesthesia with 3 % sevoflurane, with or without pretreatment of DHF (5 mg/kg/day, i.p.) for 3 consecutive days. Autonomic motor ability was assessed by open-field test, while learning and memory abilities were evaluated by the fear conditioning test. Western blotting was conducted to measure the levels of t-TrkB, p-TrkB, tau, and phosphorylated tau. Additionally, a co-immunoprecipitation assay was performed to investigate the interaction between O-GlcNAcylation and tau. RESULTS: Repeated neonatal sevoflurane exposures resulted in reduced freezing time during the context and cued fear conditioning tests in adulthood. However, pretreatment with DHF restored the freezing time to the level of the control group, indicating that DHF effectively alleviated cognitive impairments induced by neonatal sevoflurane exposure. We also observed that repeated neonatal sevoflurane exposures increased tau phosphorylation while decreasing tau O-GlcNAcylation. However, DHF pretreatment rebalanced the tau O-GlcNAcylation/phosphorylation ratio by enhancing the interaction between tau and O-GlcNAcylation. CONCLUSION: Our findings demonstrate that DHF effectively ameliorates sevoflurane-induced cognitive impairment in developing mice by restoring the balance between tau O-GlcNAcylation and phosphorylation. Therefore, this study suggests that DHF has the potential to be a therapeutic agent for treating cognitive impairment associated with anesthetics, such as sevoflurane.

Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer's disease models.

Introduction: Alzheimer's disease (AD) is a debilitating, progressive, neurodegenerative disorder characterized by the deposition of amyloid-ß (Aß) peptides and subsequent oxidative stress, resulting in a cascade of cytotoxic effects. Fangchinoline (Fan), a bisbenzylisoquinoline alkaloid isolated from traditional Chinese herb Stephania tetrandra S. Moorec, has been reported to possess multiple potent biological activities, including anti-inflammatory and antioxidant properties. However, the potential neuroprotective efficacy of Fan against AD remains unknown. Methods: N2AAPP cells, the mouse neuroblastoma N2A cells stably transfected with human Swedish mutant APP695, were served as an in vitro AD model. A mouse model of AD was constructed by microinjection of Aß1-42 peptides into lateral ventricle of WT mice. The neuroprotective effects of Fan on AD were investigated through a combination of Western blot analysis, immunoprecipitation and behavioral assessments. Results and discussion: It was found that Fan effectively attenuated the amyloidogenic processing of APP by augmenting autophagy and subsequently fostering lysosomal degradation of BACE1 in N2AAPP cells, as reflected by the decrease in P62 levels, concomitant with the increase in Beclin-1 and LC3-II levels. More importantly, Fan significantly ameliorated cognitive impairment in an Aß1-42-induced mouse model of AD via the induction of autophagy and the inhibition of oxidative stress, as evidenced by an increase in antioxidants including glutathione reductase (GR), total antioxidant capacity (T-AOC), nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and superoxide dismutase-1 (SOD-1) and a decrease in pro-oxidants including hydrogen peroxide (H2O2) and inducible nitric oxide synthase (i-NOS), coupled with a reduction in apoptosis marker, cleaved caspase-3. Taken together, our study demonstrate that Fan ameliorates cognitive dysfunction through promoting autophagy and mitigating oxidative stress, making it a potential therapeutic agent for AD.

Inhibiting NLRP3 inflammasome signaling pathway promotes neurological recovery following hypoxic-ischemic brain damage by increasing p97-mediated surface GluA1-containing AMPA receptors.

BACKGROUND: The nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is believed to be a key mediator of neuroinflammation and subsequent secondary brain injury induced by ischemic stroke. However, the role and underlying mechanism of the NLRP3 inflammasome in neonates with hypoxic-ischemic encephalopathy (HIE) are still unclear. METHODS: The protein expressions of the NLRP3 inflammasome including NLRP3, cysteinyl aspartate specific proteinase-1 (caspase-1) and interleukin-1ß (IL-1ß), the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid receptor (AMPAR) subunit, and the ATPase valosin-containing protein (VCP/p97), were determined by Western blotting. The interaction between p97 and AMPA glutamate receptor 1 (GluA1) was determined by co-immunoprecipitation. The histopathological level of hypoxic-ischemic brain damage (HIBD) was determined by triphenyltetrazolium chloride (TTC) staining. Polymerase chain reaction (PCR) and Western blotting were used to confirm the genotype of the knockout mice. Motor functions, including myodynamia and coordination, were evaluated by using grasping and rotarod tests. Hippocampus-dependent spatial cognitive function was measured by using the Morris-water maze (MWM). RESULTS: We reported that the NLRP3 inflammasome signaling pathway, such as NLRP3, caspase-1 and IL-1ß, was activated in rats with HIBD and oxygen-glucose deprivation (OGD)-treated cultured primary neurons. Further studies showed that the protein level of the AMPAR GluA1 subunit on the hippocampal postsynaptic membrane was significantly decreased in rats with HIBD, and it could be restored to control levels after treatment with the specific caspase-1 inhibitor AC-YVAD-CMK. Similarly, in vitro studies showed that OGD reduced GluA1 protein levels on the plasma membrane in cultured primary neurons, whereas AC-YVAD-CMK treatment restored this reduction. Importantly, we showed that OGD treatment obviously enhanced the interaction between p97 and GluA1, while AC-YVAD-CMK treatment promoted the dissociation of p97 from the GluA1 complex and consequently facilitated the localization of GluA1 on the plasma membrane of cultured primary neurons. Finally, we reported that the deficits in motor function, learning and memory in animals with HIBD, were ameliorated by pharmacological intervention or genetic ablation of caspase-1. CONCLUSION: Inhibiting the NLRP3 inflammasome signaling pathway promotes neurological recovery in animals with HIBD by increasing p97-mediated surface GluA1 expression, thereby providing new insight into HIE therapy.

Lack of interferon regulatory factor 3 leads to anxiety/depression-like behaviors through disrupting the balance of neuronal excitation and inhibition in mice.

Disrupting the balance of neuronal excitation and inhibition (E/I) is an important pathogenic mechanism of anxiety and depression. Interferon regulatory factor 3 (IRF3) plays a key role in the innate immune response, and activation of IRF3 triggers the expression of type I interferons and downstream interferon-stimulated genes, which are associated with anxiety and depression. However, whether IRF3 participates in the pathogenesis of anxiety/depression by regulating E/I balance remains poorly understood. Here, we reported that global knockout (KO) of IRF3 (IRF3-/-) significantly increased anxiety/depression-like behaviors, but did not affect normal spatial learning and memory. Compared with wild type (WT) control mice, the E/I balance was disrupted, as reflected by enhanced glutamatergic transmission and decreased GABAergic transmission in the neurons of hippocampal CA1 and medial prefrontal cortex (mPFC) in IRF3-KO mice. Importantly, genetic rescue of IRF3 expression by adeno-associated virus (AAV) was sufficient to alleviate anxiety/depression-like behaviors and restore the neuronal E/I balance in IRF3-KO mice. Taken together, our results indicate that IRF3 is critical in maintaining neuronal E/I balance, thereby playing an essential role in ensuring emotional stability.

Genetic inhibition of glutamate allosteric potentiation of GABAARs in mice results in hyperexcitability, leading to neurobehavioral abnormalities.

The imbalance between neuronal excitation and inhibition (E/I) in neural circuit has been considered to be at the root of numerous brain disorders. We recently reported a novel feedback crosstalk between the excitatory neurotransmitter glutamate and inhibitory γ-aminobutyric acid type A receptor (GABAAR)-glutamate allosteric potentiation of GABAAR functions through a direct binding of glutamate to the GABAAR itself. Here, we investigated the physiological significance and pathological implications of this cross-talk by generating the ß3E182G knock-in (KI) mice. We found that ß3E182G KI, while had little effect on basal GABAAR-mediated synaptic transmission, significantly reduced glutamate potentiation of GABAAR-mediated responses. These KI mice displayed lower thresholds for noxious stimuli, higher susceptibility to seizures and enhanced hippocampus-related learning and memory. Additionally, the KI mice exhibited impaired social interactions and decreased anxiety-like behaviors. Importantly, hippocampal overexpression of wild-type ß3-containing GABAARs was sufficient to rescue the deficits of glutamate potentiation of GABAAR-mediated responses, hippocampus-related behavioral abnormalities of increased epileptic susceptibility, and impaired social interactions. Our data indicate that the novel crosstalk among excitatory glutamate and inhibitory GABAAR functions as a homeostatic mechanism in fine-tuning neuronal E/I balance, thereby playing an essential role in ensuring normal brain functioning.

Octadecaneuropeptide Ameliorates Cognitive Impairments Through Inhibiting Oxidative Stress in Alzheimer's Disease Models.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-ß peptide (Aß) deposition. Aß accumulation induces oxidative stress, leading to mitochondrial dysfunction, apoptosis, and so forth. Octadecaneuropeptide (ODN), a diazepam-binding inhibitor (DBI)-derived peptide, has been reported to have antioxidant properties. However, it is unclear whether ODN has neuroprotective effects in AD. OBJECTIVE: To profile the potential effects of ODN on AD. METHODS: We established a mouse model of AD via microinjection of Aß in the lateral ventricle. Utilizing a combination of western blotting assays, electrophysiological recordings, and behavioral tests, we investigated the neuroprotective effects of ODN on AD. RESULTS: DBI expression was decreased in AD model mice and cells. Meanwhile, ODN decreased Aß generation by downregulating amyloidogenic AßPP processing in HEK-293 cells stably expressing human Swedish mutant APP695 and BACE1 (2EB2). Moreover, ODN could inhibit Aß-induced oxidative stress in primary cultured cells and mice, as reflected by a dramatic increase in antioxidants and a decrease in pro-oxidants. We also found that ODN could reduce oxidative stress-induced apoptosis by restoring mitochondrial membrane potential, intracellular Ca2+ and cleaved caspase-3 levels in Aß-treated primary cultured cells and mice. More importantly, intracerebroventricular injection of ODN attenuated cognitive impairments as well as long-term potentiation in Aß-treated mice. CONCLUSION: These results suggest that ODN may exert a potent neuroprotective effect against Aß-induced neurotoxicity and memory decline via its antioxidant effects, indicating that ODN may be a potential therapeutic agent for AD.

Glutamate and GABAA receptor crosstalk mediates homeostatic regulation of neuronal excitation in the mammalian brain.

Maintaining a proper balance between the glutamate receptor-mediated neuronal excitation and the A type of GABA receptor (GABAAR) mediated inhibition is essential for brain functioning; and its imbalance contributes to the pathogenesis of many brain disorders including neurodegenerative diseases and mental illnesses. Here we identify a novel glutamate-GABAAR interaction mediated by a direct glutamate binding of the GABAAR. In HEK293 cells overexpressing recombinant GABAARs, glutamate and its analog ligands, while producing no current on their own, potentiate GABA-evoked currents. This potentiation is mediated by a direct binding at a novel glutamate binding pocket located at the α+/ß- subunit interface of the GABAAR. Moreover, the potentiation does not require the presence of a γ subunit, and in fact, the presence of γ subunit significantly reduces the potency of the glutamate potentiation. In addition, the glutamate-mediated allosteric potentiation occurs on native GABAARs in rat neurons maintained in culture, as evidenced by the potentiation of GABAAR-mediated inhibitory postsynaptic currents and tonic currents. Most importantly, we found that genetic impairment of this glutamate potentiation in knock-in mice resulted in phenotypes of increased neuronal excitability, including decreased thresholds to noxious stimuli and increased seizure susceptibility. These results demonstrate a novel cross-talk between excitatory transmitter glutamate and inhibitory GABAAR. Such a rapid and short feedback loop between the two principal excitatory and inhibitory neurotransmission systems may play a critical homeostatic role in fine-tuning the excitation-inhibition balance (E/I balance), thereby maintaining neuronal excitability in the mammalian brain under both physiological and pathological conditions.

Octadecaneuropeptide Alleviates Motor and Cognitive Impairments in Neonatal Rats Following Hypoxic-Ischemic Brain Damage.

Hypoxic-ischemic brain damage (HIBD) is among the leading causes of neonatal brain injury. ODN, a peptide derived from diazepam-binding inhibitor (DBI), has potent antioxidant and anti-apoptotic properties. It remains unclear, however, whether ODN is an effective treatment for HIBD. Here, we reported that treatment with ODN (10 ng/day, i.c.v.) alleviated the deficits in myodynamia and motor coordination and cognitive functions in HIBD. Meanwhile, ODN prevented the neuronal loss in the cortex and hippocampus in HIBD rats. In addition, ODN decreased ROS by generating less oxidants and more antioxidants, as reflected by a dramatic increase in total antioxidant capacity, glutathione reductase, and catalase and a marked decrease in H2O2 and total nitric oxide synthase. Collectively, these data show ODN alleviates neuron injury and motor and memory deficits by attenuating ROS production and could be used as a novel molecular for treating HIBD.

A stable liquid-solid interface of a lithium metal anode enabled by micro-region meshing.

Although lithium metal is regarded as the most promising anode for high energy density lithium ion batteries, the unstable solid-liquid interface during cycling severely shortens the battery lifetime. The Li deposition behavior is greatly influenced by the current density distribution on the surface of the electrode, which is significantly associated with the electrode structure. A well-designed electrode structure plays a key role in stabilizing the solid-liquid interface of the Li metal anode. In this work, a lithiophilic honeycomb-like Ni3N nanosheet array modified Ni foam (Ni3N@NF) is prepared to stabilize the lithium metal anode. The honeycomb-like Ni3N nanosheet arrays divide the surface of Ni foam into numerous micro-regions, enabling Li to independently deposit in each mesh. Besides, Li3N is generated resulting from the in situ reaction between Li and Ni3N, improving the transportation of Li-ions. Consequently, a symmetrical cell of Ni3N@NF-Li||Ni3N@NF-Li achieves stable Li plating/stripping behavior for over 1500 h at a current density of 1 mA cm-2. Besides, a full cell of Ni3N@NF-Li||LiFePO4 exhibits enhanced cycling stability and outstanding rate performance.

Dihydroartemisinin Induces O-GlcNAcylation and Improves Cognitive Function in a Mouse Model of Tauopathy.

BACKGROUND: Tauopathies are a group of neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau pathology. Hyperphosphorylation modification promotes tau protein misfolding and aggregation into neurofibrillary tangles, leading to impairments of synaptic plasticity and learning and memory. However, very limited therapeutic strategies are available. OBJECTIVE: In the present study, we wanted to investigate the potential effects of Dihydroartemisinin (DHA) on tauopathies. METHODS: We constructed adeno-associated virus carrying hTau cDNA (AAVhTau) to establish a mouse model of tauopathy through intrahippocampal microinjection. Using a combination of behavioral test, electrophysiological recording, and western blotting assay, we examined the neuroprotective effects of DHA on learning and memory deficits in mice with tauopathy. RESULTS: DHA improved learning and memory and increased hippocampal CA1 long-term potentiation (LTP) in mice overexpressed human tau (hTau) in the hippocampus. More importantly, further study revealed that DHA could induce protein O-GlcNAcylation modification and reduce protein phosphorylation. O-GlcNAc transferase inhibitor alloxan could suppress DHA-induced protein O-GlcNAcylation, and subsequently prevent therapeutic effect of DHA on the deficits of learning and memory as well as synaptic plasticity in hTau mice. CONCLUSION: These results indicate that DHA may exert neuroprotective role in tauopathy through a crosstalk between O-GlcNAcylation and phosphorylation, suggesting a potential therapeutic for learning and memory deficits associated with tau pathology.

Vanadium Pentoxide Nanofibers/Carbon Nanotubes Hybrid Film for High-Performance Aqueous Zinc-Ion Batteries.

Aqueous zinc-ion batteries (ZIBs) with the characteristics of low production costs and good safety have been regarded as ideal candidates for large-scale energy storage applications. However, the nonconductive and non-redox active polymer used as the binder in the traditional preparation of electrodes hinders the exposure of active sites and limits the diffusion of ions, compromising the energy density of the electrode in ZIBs. Herein, we fabricated vanadium pentoxide nanofibers/carbon nanotubes (V2O5/CNTs) hybrid films as binder-free cathodes for ZIBs. High ionic conductivity and electronic conductivity were enabled in the V2O5/CNTs film due to the porous structure of the film and the introduction of carbon nanotubes with high electronic conductivity. As a result, the batteries based on the V2O5/CNTs film exhibited a higher capacity of 390 mAh g-1 at 1 A g-1, as compared to batteries based on V2O5 (263 mAh g-1). Even at 5 A g-1, the battery based on the V2O5/CNTs film maintained a capacity of 250 mAh g-1 after 2000 cycles with a capacity retention of 94%. In addition, the V2O5/CNTs film electrode also showed a high energy/power density (e.g., 67 kW kg-1/267 Wh kg-1). The capacitance response and rapid diffusion coefficient of Zn2+ (~10-8 cm-2 s-1) can explain the excellent rate capability of V2O5/CNTs. The vanadium pentoxide nanofibers/carbon nanotubes hybrid film as binder-free cathodes showed a high capability and a stable cyclability, demonstrating that it is highly promising for large-scale energy storage applications.

Aagab acts as a novel regulator of NEDD4-1-mediated Pten nuclear translocation to promote neurological recovery following hypoxic-ischemic brain damage.

Hypoxic-ischemic encephalopathy (HIE) is a main cause of mortality and severe neurologic impairment in the perinatal and neonatal period. However, few satisfactory therapeutic strategies are available. Here, we reported that a rapid nuclear translocation of phosphatase and tensin homolog deleted on chromosome TEN (PTEN) is an essential step in hypoxic-ischemic brain damage (HIBD)- and oxygen-glucose deprivation (OGD)-induced neuronal injures both in vivo and in vitro. In addition, we found that OGD-induced nuclear translocation of PTEN is dependent on PTEN mono-ubiquitination at the lysine 13 residue (K13) that is mediated by neural precursor cell expressed developmentally downregulated protein 4-1 (NEDD4-1). Importantly, we for the first time identified α- and γ-adaptin binding protein (Aagab) as a novel NEDD4-1 regulator to regulate the level of NEDD4-1, subsequently mediating Pten nuclear translocation. Finally, we demonstrated that genetic upregulation of Aagab or application of Tat-K13 peptide (a short interference peptide that flanks K13 residue of PTEN) not only reduced Pten nuclear translocation, but also significantly alleviated the deficits of myodynamia, motor and spatial learning and memory in HIBD model rats. These results suggest that Aagab may serve as a regulator of NEDD4-1-mediated Pten nuclear translocation to promote functional recovery following HIBD in neonatal rats, and provide a new potential therapeutic target to guide the clinical treatment for HIE.

Uniform Zn Deposition Achieved by Ag Coating for Improved Aqueous Zinc-Ion Batteries.

Aqueous zinc-ion batteries (ZIBs) are considered as a promising energy storage system due to their low cost and high safety merits. However, they suffer from the challenge of uncontrollable dendrite growth due to a non-uniform zinc deposition, which increases internal resistance and causes battery failure. Herein, Ag coating fabricated by a facile surface chemistry route on zinc metal was developed to guide uniform zinc deposition. Ag-coated Zn shows improved electrolyte wettability, a small zinc deposition overpotential, and fast kinetics for zinc deposition/dissolution. Direct optical visualization and scanning electron microscopy images show uniform zinc deposition due to the introduction of Ag coating. As a result, the Ag-coated Zn anode can sustain up to 1450 h of repeated plating/stripping with a low overpotential in symmetric cells at a current density of 0.2 mA cm-2, while an improved performance is realized for full cells paired with a V2O5-based cathode. This work provides a facile and effective approach to improve the electrochemical performance of ZIBs.

Liquiritigenin Decreases Aß Levels and Ameliorates Cognitive Decline by Regulating Microglia M1/M2 Transformation in AD Mice.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is currently incurable. Amyloid ß protein (Aß) deposition is the main pathogenesis of AD, and many studies have shown that Aß accumulation is toxic to neurons, leading to the inflammatory reaction, neuronal apoptosis, and neurofibrillary tangles. Thus, reducing Aß levels might be a potential therapeutic strategy for AD. Liquiritigenin (LG), a dihydroflavone monomer compound extracted from natural plant licorice, has a variety of biological activities such as antioxidant, anti-tumor, anti-inflammatory and anti-virus. However, the exact function of LG in the pathogenesis of AD is elusive. Here, we reported that LG could significantly attenuate neuronal apoptosis in Aß-induced N2A cells and APP/PS1 transgenic mice. Our in vivo and in vitro studies revealed that LG could alleviate the inflammation response, reflected by the reduction of NLRP3 and cleaved caspase-1. Meanwhile, we also found that LG was able to shift M1 type microglia towards M2 type microglia in Aß-induced BV2 cells and AD mice. Furthermore, LG could reduce the Aß levels by decreasing APP processing and accelerating Aß clearance in AD mice. More importantly, daily treatment of LG (30 mg/kg day) for 90 days dramatically ameliorated the spatial learning and memory of AD mice. Taken together, these results suggest that LG can reduce the Aß levels by regulating the M1/M2 transformation of microglia, thereby reversing memory decline during AD development, suggesting that LG may be a potential therapeutic agent for treating AD.

Nicotine Promotes AßPP Nonamyloidogenic Processing via RACK1-Dependent Activation of PKC in SH-SY5Y-AßPP695 Cells.

BACKGROUND: Accumulation of amyloid-ß (Aß) peptides, generated from amyloid-ß precursor protein (AßPP) amyloidogenic processing, is one of the most salient disease hallmarks of Alzheimer's disease (AD). Nicotine is able to promote α-secretase-mediated AßPP nonamyloidogenic processing and increase the release of sAßPPα and C-terminal fragment of 83 amino acids (C83). However, the potential molecular mechanism remains elusive. OBJECTIVE: The aim of the present study was to investigate the effect of nicotine on AßPP processing in SH-SY5Y cells that stably express human Swedish mutant AßPP695 (SH-SY5Y-AßPP695). METHODS: The expression of AßPP and its C-terminal fragments including C99, C89, and C83, was measured in SH-SY5Y-AßPP695 cells treated with nicotine for 6 h. Protein kinase C (PKC) antagonist Ro30-8220 or agonist PMA was used to determine the role of PKC in AßPP processing. Lentivirus-mediated shRNA targeting receptor for activated C-kinase 1 (RACK1) gene was added into the media to knockdown RACK1 expression, and then AßPP processing was examined. RESULTS: The results showed that 6 h of nicotine exposure increased the expression of α-secretase (ADAM10) and C83 in a dose dependent manner. While the ß-secretase (BACE1), AßPP amyloidogenic processing products C89 and C99 as well as Aß peptides (including Aß40 and Aß42) remained unchanged. We also found that nicotine elevated the expression of phosphorylated PKC (P-PKC) and RACK1 on the cytomembrane. PKC antagonist Ro30-8220 treatment prevented the increase of ADAM10 and C83 by nicotine. Genetic knockdown RACK1 significantly inhibited P-PKC, and consequently abolished the increase of ADAM10 and C83 by nicotine. CONCLUSION: Taken together, these results indicate that nicotine effectively promotes AßPP nonamyloidogenic processing via RACK1-dependent activation of PKC in SH-SY5Y-AßPP695 cells and could be a potential molecule for AD treatment.

TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common causes of neurodegenerative diseases in the elderly. The accumulation of amyloid-ß (Aß) peptides is one of the pathological hallmarks of AD and leads to the impairments of synaptic plasticity and cognitive function. The transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel, is involved in synaptic plasticity and memory. However, the role of TRPV1 in AD pathogenesis remains largely elusive. Here, we reported that the expression of TRPV1 was decreased in the brain of APP23/PS45 double transgenic AD model mice. Genetic upregulation of TRPV1 by adeno-associated virus (AAV) inhibited the APP processing and Aß deposition in AD model mice. Meanwhile, upregulation of TRPV1 ameliorated the deficits of hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory through inhibiting GluA2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) endocytosis. Furthermore, pharmacological activation of TRPV1 by capsaicin (1 mg/kg, i.p.), an agonist of TRPV1, dramatically reversed the impairments of hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, these results indicate that TRPV1 activation effectively ameliorates cognitive and synaptic functions through inhibiting AMPAR endocytosis in AD model mice and could be a novel molecule for AD treatment.

MKP-1 reduces Aß generation and alleviates cognitive impairments in Alzheimer's disease models.

Mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is an essential negative regulator of MAPKs by dephosphorylating MAPKs at both tyrosine and threonine residues. Dysregulation of the MAPK signaling pathway has been associated with Alzheimer's disease (AD). However, the role of MKP-1 in AD pathogenesis remains elusive. Here, we report that MKP-1 levels were decreased in the brain tissues of patients with AD and an AD mouse model. The reduction in MKP-1 gene expression appeared to be a result of transcriptional inhibition via transcription factor specificity protein 1 (Sp1) cis-acting binding elements in the MKP-1 gene promoter. Amyloid-ß (Aß)-induced Sp1 activation decreased MKP-1 expression. However, upregulation of MKP-1 inhibited the expression of both Aß precursor protein (APP) and ß-site APP-cleaving enzyme 1 by inactivating the extracellular signal-regulated kinase 1/2 (ERK)/MAPK signaling pathway. Furthermore, upregulation of MKP-1 reduced Aß production and plaque formation and improved hippocampal long-term potentiation (LTP) and cognitive deficits in APP/PS1 transgenic mice. Our results demonstrate that MKP-1 impairment facilitates the pathogenesis of AD, whereas upregulation of MKP-1 plays a neuroprotective role to reduce Alzheimer-related phenotypes. Thus, this study suggests that MKP-1 is a novel molecule for AD treatment.