Chronic but not acute nicotine treatment ameliorates acute inflammation-induced working memory impairment by increasing CRTC1 and HCN2 in adult male mice.

BACKGROUND: Systemic inflammation in which lipopolysaccharide (LPS) is released into circulation can cause cognitive dysfunction and we have previously shown that LPS impaired working memory (WM) which refers to the ability to guide incoming behavior by retrieving recently acquired information. However, the mechanism is not very clear, and currently, there is no approved strategy to improve inflammation-induced WM deficit. Notably, epidemiological studies have demonstrated a lower occurrence rate of inflammatory-related diseases in smoking patients, suggesting that inflammation-induced WM impairment may be improved by nicotine treatment. Here, our object is to investigate the effect and potential mechanisms of acute and chronic nicotine treatment on LPS-produced WM deficiency. METHODS: Delayed alternation T-maze task (DAT) was applied for evaluating WM which includes both the short-term information storage and the ability to correct errors in adult male mice. Immunofluorescence staining and immunoblotting were used for assessing the levels and distribution of CREB-regulated transcription coactivator 1 (CRTC1) and hyperpolarization-activated cation channels 2 (HCN2) in the medial prefrontal cortex (mPFC) and hippocampus. Quantitative PCR and ELISA were employed for analyzing the mRNA and protein levels of TNF-α and IL-1ß. RESULTS: Our results revealed that administration of LPS (i.p.) at a dose of 0.5 mg/kg significantly produced WM impairment in the DAT task accompanied by an increase in IL-1ß and TNF-α expression in the mPFC. Moreover, intra-mPFC infusion of IL-1Ra, an IL-1 antagonist, markedly alleviated LPS-induced WM deficiency. More important, chronic (2 weeks) but not acute nicotine (0.2 mg/kg, subcutaneous) treatment significantly alleviated LPS-induced WM deficiency by upregulating CRTC1 and HCN2. Of note, intra-mPFC infusion of HCN blocker ZD7288 produced significant WM deficiency. CONCLUSIONS: In summary, in this study, we show that chronic nicotine treatment ameliorates acute inflammation-induced working memory deficiency by increasing CRTC1 and HCN2 in adult male mice.

Analysis of the influences of social isolation on cognition and the therapeutic potential of deep brain stimulation in a mouse model.

Background: Social interaction is a fundamental human need. Social isolation (SI) can have negative effects on both emotional and cognitive function. However, it is currently unclear how age and the duration of SI affect emotion and recognition function. In addition, there is no specific treatment for the effects of SI. Methods: The adolescence or adult mice were individually housed in cages for 1, 6 or 12 months and for 2 months to estabolish SI mouse model. We investigated the effects of SI on behavior in mice at different ages and under distinct durations of SI, and we explored the possible underlying mechanisms. Then we performed deep brain stimulation (DBS) to evaluate its influences on SI induced behavioral abnormalities. Results: We found that social recognition was affected in the short term, while social preference was damaged by extremely long periods of SI. In addition to affecting social memory, SI also affects emotion, short-term spatial ability and learning willingness in mice. Myelin was decreased significantly in the medial prefrontal cortex (mPFC) and dorsal hippocampus of socially isolated mice. Cellular activity in response to social stimulation in both areas was impaired by social isolation. By stimulating the mPFC using DBS, we found that DBS alleviated cellular activation disorders in the mPFC after long-term SI and improved social preference in mice. Conclusion: Our results suggest that the therapeutic potential of stimulating the mPFC with DBS in individuals with social preference deficits caused by long-term social isolation, as well as the effects of DBS on the cellular activity and density of OPCs.

Nicotine Treatment Ameliorates Blood-Brain Barrier Damage After Acute Ischemic Stroke by Regulating Endothelial Scaffolding Protein Pdlim5.

Analysis of a National Institutes of Health (NIH) trial shows that cigarette smoking protected tissue plasminogen activator (tPA)-treated patients from hemorrhage transformation (HT); however, the underlying mechanism is not clear. Damage to the integrity of the blood-brain barrier (BBB) is the pathological basis of HT. Here, we investigated the molecular events of BBB damage after acute ischemic stroke (AIS) using in vitro oxygen-glucose deprivation (OGD) and in vivo mice middle cerebral artery occlusion (MCAO) models. Our results showed that the permeability of bEND.3 monolayer endothelial cells was significantly increased after being exposed to OGD for 2 h. Mice were subjected to 90-min ischemia with 45-min reperfusion, and BBB integrity was significantly damaged, accompanied by tight junction protein occludin degradation, downregulation of microRNA-21 (miR-21), transforming growth factor-ß (TGF-ß), phosphorylated Smad (p-Smad), plasminogen activator inhibitor-1 (PAI-1), and the upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that has been shown to regulate TGF-ß-Smad3 pathway. In addition, pretreatment with two-week nicotine significantly reduced AIS-induced BBB damage and its associated protein dysregulation via downregulating Pdlim5. Notably, AIS did not significantly induce BBB damage in Pdlim5 deficit mice, but overexpression of Pdlim5 in the striatum with adeno-associated virus produced BBB damage and associated protein dysregulation which could be ameliorated by two-week nicotine pretreatment. More important, AIS induced a significant miR-21 decrease, and miR-21 mimics treatment decreased AIS-induced BBB damage by decreasing Pdlim5. Together, these results demonstrate that nicotine treatment alleviates the AIS-compromised integrity of BBB by regulating Pdlim5.

CRTC1 is a potential target to delay aging-induced cognitive deficit by protecting the integrity of the blood-brain barrier via inhibiting inflammation.

Aging can cause attenuation in the functioning of multiple organs, and blood-brain barrier (BBB) breakdown could promote the occurrence of disorders of the central nervous system during aging. Since inflammation is considered to be an important factor underlying BBB injury during aging, vascular endothelial cell senescence serves as a critical pathological basis for the destruction of BBB integrity. In the current review, we have first introduced the concepts related to aging-induced cognitive deficit and BBB integrity damage. Thereafter, we reviewed the potential relationship between disruption of BBB integrity and cognition deficit and the role of inflammation, vascular endothelial cell senescence, and BBB injury. We have also briefly introduced the function of CREB-regulated transcription co-activator 1 (CRTC1) in cognition and aging-induced CRTC1 changes as well as the critical roles of CRTC1/cyclooxygenase-2 (COX-2) in regulating inflammation, endothelial cell senescence, and BBB injury. Finally, the underlying mechanisms have been summarized and we propose that CRTC1 could be a promising target to delay aging-induced cognitive deficit by protecting the integrity of BBB through promoting inhibition of inflammation-mediated endothelial cell senescence.

Transcranial low-intensity ultrasound stimulation for treating central nervous system disorders: A promising therapeutic application.

Transcranial ultrasound stimulation is a neurostimulation technique that has gradually attracted the attention of researchers, especially as a potential therapy for neurological disorders, because of its high spatial resolution, its good penetration depth, and its non-invasiveness. Ultrasound can be categorized as high-intensity and low-intensity based on the intensity of its acoustic wave. High-intensity ultrasound can be used for thermal ablation by taking advantage of its high-energy characteristics. Low-intensity ultrasound, which produces low energy, can be used as a means to regulate the nervous system. The present review describes the current status of research on low-intensity transcranial ultrasound stimulation (LITUS) in the treatment of neurological disorders, such as epilepsy, essential tremor, depression, Parkinson's disease (PD), and Alzheimer's disease (AD). This review summarizes preclinical and clinical studies using LITUS to treat the aforementioned neurological disorders and discusses their underlying mechanisms.

Insights into water freezing from classical nucleation theory.

Water freezing is a crucial physical phenomenon. The process of ice formation, and the estimation of the ice nucleation rate also have important applications. However, until now, the experimental phenomenon of rapid freezing of water in nanoseconds has not been fully explained theoretically, and the physics underlying the experimental phenomenon has still not been revealed. In this work, combining classical nucleation theory with Mie theory, a kinetic model is developed that reproduces for the first time the experimental phenomenon of decreasing transmissivity. The process of ice formation (nucleation, growth and engulfment) has been revealed. In the process of theoretical derivation, the Zel'dovich-Frenkel (ZF) equation is developed, indicating a limit to the phase transition driving force |Δµ|/(kBT) ≤ 1. By analyzing the experimental and simulation results, it is suggested that the change in the transparency of the sample may be caused by the ice/vacuum interface scattering. In addition, during the rapid phase transition, it was found that the phase transition continues to occur even after phase fraction normalization. Finally, the approximate formula between the nucleation rate and sample transparency is given. This formula can predict the change of sample transparency during phase transition and provides a way to measure the nucleation rate. The results presented here give an insight into the phase transition kinetics, and the methodology may also work for the phase transitions of other materials.

Mixed cellulose ester membrane as an ion redistributor to stabilize zinc anode in aqueous zinc ion batteries.

Aqueous zinc-ion batteries (AZBs) with high energy density, low cost and environmental characteristics, have become the promising device for energy storage. However, uncontrolled zinc dendrite growth remains an impediment to the popularization of AZBs. The unrestricted two-dimensional (2D) ions diffusion is the main cause of the above defect. In this work, mixed cellulose ester (MCE) membrane is proposed as the separator. A dense homogeneous pore structure can achieve a physical shunting effect on ion diffusion, which can control and homogenize the ion motion. Further, the mechanism of this physical pore effect is confirmed by comparing the behavior of Zn deposition in MCE systems with different pore sizes but the same composition. As conjectured, a membrane with a smaller pore size is more favorable. In addition, the MCE contains many polar oxygen-containing functional groups that can facilitate and modulate ion diffusion through coordination. This chemical ion guiding effect, together with the above physical pore effect, gives the separator the ability to suppress dendrite formation. Zn/Zn symmetric cells with this membrane exhibit ultralong cycle life exceeding 1250 h at 0.5 mA cm-2 and 1000 h at 5 mA cm-2. And the Zn//MnO2 battery presents excellent cycle stability for more than 500 cycles with a capacity retention of 90.67%. This work proposes MCE separators and reveals their coordinated regulation of physical and chemical effects on metal-based anodes. This will shed light on the development of high-performance separators and AZBs.

Nicotine's effect on cognition, a friend or foe?

Tobacco smoking is a preventable cause of morbidity and mortality throughout the world. Smoking comes in form of absorption of many compounds, among which nicotine is the main psychoactive component of tobacco and its positive and negative reinforcement effects are proposed to be the key mechanism for the initiation and maintenance of smoking. Growing evidence suggests that the cognitive enhancement effects of nicotine may also contribute to the difficulty of quitting smoking, especially in individuals with psychiatric disorders. In this review, we first introduce the beneficial effect of nicotine on cognition including attention, short-term memory and long-term memory. We next summarize the beneficial effect of nicotine on cognition under pathological conditions, including Alzheimer's disease, Parkinson's disease, Schizophrenia, Stress-induced Anxiety, Depression, and drug-induced memory impairment. The possible mechanism underlying nicotine's effect is also explored. Finally, nicotine's detrimental effect on cognition is discussed, including in the prenatal and adolescent periods, and high-dose nicotine- and withdrawal-induced memory impairment is emphasized. Therefore, nicotine serves as both a friend and foe. Nicotine-derived compounds could be a promising strategy to alleviate neurological disease-associated cognitive deficit, however, due to nicotine's detrimental effect, continued educational programs and public awareness campaigns are needed to reduce tobacco use among pregnant women and smoking should be quitted even if it is e-cigarette, especially for the adolescents.

Distributed Li-Ion Flux Enabled by Sulfonated Covalent Organic Frameworks for High-Performance Lithium Metal Anodes.

Metallic Li is considered the most promising anode material for high-energy-density batteries owing to its high theoretical capacity and low electrochemical potential. However, inhomogeneous lithium deposition and uncontrollable growth of lithium dendrites result in low lithium utilization, rapid capacity fading, and poor cycling performance. Herein, two sulfonated covalent organic frameworks (COFs) with different sulfonated group contents are synthesized as the multifunctional interlayers in lithium metal batteries. The sulfonic acid groups in the pore channels can serve as Li-anchoring sites that effectively coordinate Li ions. These periodically arranged subunits significantly guide uniform Li-ion flux distribution, guarantee smooth Li deposition, and reduce lithium dendrite formation. Consequently, these characteristics afford an excellent quasi-solid-state electrolyte with a high ionic conductivity of 1.9 × 10-3  S  cm-1 at room temperature and a superior Li++ transference number of 0.91. A Li/LiFePO4 battery with the COF-based electrolyte exhibited dendrite-free Li deposition during the charge process, accompanied by no capacity decay after 100 cycles at 0.1 C.

Nicotine pretreatment alleviates MK-801-induced behavioral and cognitive deficits in mice by regulating Pdlim5/CRTC1 in the PFC.

Increasing evidence shows that smoking-obtained nicotine is indicated to improve cognition and mitigate certain symptoms of schizophrenia. In this study, we investigated whether chronic nicotine treatment alleviated MK-801-induced schizophrenia-like symptoms and cognitive impairment in mice. Mice were injected with MK-801 (0.2 mg/kg, i.p.), and the behavioral deficits were assessed using prepulse inhibition (PPI) and T-maze tests. We showed that MK-801 caused cognitive impairment accompanied by increased expression of PDZ and LIM domain 5 (Pdlim5), an adaptor protein that is critically associated with schizophrenia, in the prefrontal cortex (PFC). Pretreatment with nicotine (0.2 mg · kg-1 · d-1, s.c., for 2 weeks) significantly ameliorated MK-801-induced schizophrenia-like symptoms and cognitive impairment by reversing the increased Pdlim5 expression levels in the PFC. In addition, pretreatment with nicotine prevented the MK-801-induced decrease in CREB-regulated transcription coactivator 1 (CRTC1), a coactivator of CREB that plays an important role in cognition. Furthermore, MK-801 neither induced schizophrenia-like behaviors nor decreased CRTC1 levels in the PFC of Pdlim5-/- mice. Overexpression of Pdlim5 in the PFC through intra-PFC infusion of an adreno-associated virus AAV-Pdlim5 induced significant schizophrenia-like symptoms and cognitive impairment. In conclusion, chronic nicotine treatment alleviates schizophrenia-induced memory deficits in mice by regulating Pdlim5 and CRTC1 expression in the PFC.

Engineering the interface of organic/inorganic composite solid-state electrolyte by amino effect for all-solid-state lithium batteries.

Composite solid-state electrolyte (CSSE) with integrated strengths avoids the weaknesses of organic and inorganic electrolytes, and thus become a better choice for all-solid-state lithium battery (ASSLB). However, the poor dispersion of inorganic fillers and the organic/inorganic nature difference leads to their interface incompatibility, which greatly destroys the performance of CSSE and ASSLB. Herein, silane coupling agent (SCA) aminopropyl triethoxysilane (ATS) is introduced to tailor the organic/inorganic interfaces in CSSE by the common chemical bridging effect of SCA and the special amino effect (hydrogen bond and lone pair electron effects). It is found that the hydrogen bond interaction between -NH2 and polyethylene oxide (PEO) enhances their interface interaction. And the lone pair electrons on nitrogen atom allow it to react with solvent acetonitrile and promote the uniform dispersion of ceramic fillers. Moreover, the lone pair electrons can complex with Li+, which promotes the dissociation of Li salts, uniforms Li+ diffusion and inhibits the Li dendrite. Thanks to the above merits, the interface compatibility and stability of organic/inorganic CSSE are much enhanced by innovatively introducing ATS, showing high ionic conductivity and superior mechanical/thermal stability. The ASSLB with this modified CSSE exhibits excellent electrochemical performance with a reversible capacity of 140.9 mAh g-1 and a capacity retention of 94.4% after 280 cycles. These achievements offer a new insight into improving the stability of organic/inorganic CSSE interface and promoting their applicability into ASSLB.

The Stem Cell Potential of O-2A Lineage Astroglia.

Astrocytes are the most common glial type in the central nervous system. They play pivotal roles in neurophysiological and neuropathological processes. Mounting evidence indicates that astrocytes may act as neural stem cells and contribute to adult neurogenesis. In previous reports, freshly isolated O-2A progenitors were shown to revert to neural stem-like cells (NSLCs) when cultured with a serum-containing glial medium or bone morphogenic proteins for 3 days and with basic fibroblast growth factor consecutively. NSLCs possess self-renewal and multipotential capacities that can give rise to neurons and glial cells, which suggests that they have stem cell-like properties. However, the underlying molecular mechanisms and cell fate commitment when exposed to a neural conditioned medium remain obscure. In this study, we demonstrated that NSLCs grown in the serum-containing neurobasal medium can differentiate into induced neural-like cells (iNLCs). It was noteworthy that astroglia mixed in these cells, particularly in iNLCs, were gradually replaced by neural phenotypes during this glia-neuron conversion. Remarkably, these glial cells can maintain high levels of proliferation and self-renewal ability by activating the NF-κB and MAPK signals. Finally, we found that Notch, STAT3, autophagy, bHLH, and Wnt signals appear to be critical modulators of these intricate events. Altogether, these data demonstrate that O-2A lineage astroglia can function as neural stem cells and display neurogenic plasticity. Dissecting the regulatory pathways involved in these processes is essential to the understanding of glial cell fate and its precise functions. This finding may foster a better understanding of astrocytic heterogeneity and lead to innovative ways to readily apply stem-like astroglia cells as candidate cell sources for neural repair.

TRIM32 Deficiency Impairs the Generation of Pyramidal Neurons in Developing Cerebral Cortex.

Excitatory-inhibitory imbalance (E/I) is a fundamental mechanism underlying autism spectrum disorders (ASD). TRIM32 is a risk gene genetically associated with ASD. The absence of TRIM32 causes impaired generation of inhibitory GABAergic interneurons, neural network hyperexcitability, and autism-like behavior in mice, emphasizing the role of TRIM32 in maintaining E/I balance, but despite the description of TRIM32 in regulating proliferation and differentiation of cultured mouse neural progenitor cells (NPCs), the role of TRIM32 in cerebral cortical development, particularly in the production of excitatory pyramidal neurons, remains unknown. The present study observed that TRIM32 deficiency resulted in decreased numbers of distinct layer-specific cortical neurons and decreased radial glial cell (RGC) and intermediate progenitor cell (IPC) pool size. We further demonstrated that TRIM32 deficiency impairs self-renewal of RGCs and IPCs as indicated by decreased proliferation and mitosis. A TRIM32 deficiency also affects or influences the formation of cortical neurons. As a result, TRIM32-deficient mice showed smaller brain size. At the molecular level, RNAseq analysis indicated reduced Notch signalling in TRIM32-deficient mice. Therefore, the present study indicates a role for TRIM32 in pyramidal neuron generation. Impaired generation of excitatory pyramidal neurons may explain the hyperexcitability observed in TRIM32-deficient mice.

Modulation of α7nAchR by Melatonin Alleviates Ischemia and Reperfusion-Compromised Integrity of Blood-Brain Barrier Through Inhibiting HMGB1-Mediated Microglia Activation and CRTC1-Mediated Neuronal Loss.

The only food and drug administration (FDA)-approved drug currently available for the treatment of acute ischemic stroke is tissue plasminogen activator (tPA), yet the therapeutic benefits of this drug are partially outweighed by the increased risk of hemorrhagic transformation (HT). Analysis of the NIH trial has shown that cigarette smoking protected tPA-treated patients from HT; however, the underlying mechanism is not clear. Nicotinic acetylcholine receptors (nAChR) has shown anti-inflammatory effect and modulation nAChR could be a strategy to reduce ischemia/reperfusion-induced blood-brain barrier (BBB) damage. Since melatonin could regulate the expression of α7nAchR and melatonin's neuroprotective effect against ischemic injury is mediated via α7nAChR modulation, here, we aim to test the hypothesis that melatonin reduces ischemia and reperfusion (I/R)-induced BBB damage through modulation of α7nACh receptor (α7nAChR). Mice were subjected to 1.5 h ischemia and 24 h reperfusion and at the onset of reperfusion, mice received intraperitoneal administration (i.p.) of either drug or saline. Mice were randomly assigned into five groups: Saline; α7nAChR agonist PNU282987; Melatonin; Melatonin+Methyllycaconitine (MLA, α7nAChR antagonist), and MLA group. BBB permeability was assessed by detecting the extravasation of Evan's blue and IgG. Our results showed that I/R significantly increased BBB permeability accompanied by occludin degradation, microglia activation, and high mobility group box 1 (HMGB1) release from the neuron. In addition, I/R significantly induced neuronal loss accompanied by the decrease of CREB-regulated transcriptional coactivator 1 (CRTC1) and p-CREB expression. Melatonin treatment significantly inhibited the above changes through modulating α7nAChR. Taken together, these results demonstrate that melatonin provides a protective effect on ischemia/reperfusion-induced BBB damage, at least in part, depending on the modulation of α7nAChR.

Suppressing the P2 - O2 phase transformation and Na+/vacancy ordering of high-voltage manganese-based P2-type cathode by cationic codoping.

High-voltage and low-cost manganese-based P2-type oxides show real promise as promising cathode for sodium-ion batteries (SIBs). But the P2 - O2 phase transformation and Na+/vacancy ordering results in the inferior structural stability and Na+ diffusion coefficient, which further leads to rapid decay of capacity and poor rate capability. Herein, in consideration of the synergetic effects of dual cationic doping, electrochemically inactive Li+ and active Co3+ codoping are proposed to solve the above issues. The novel two-step doping strategy, Co doping during synthesis of precursors via coprecipitation reaction followed by Li doping during solid-state reaction, are rationally developed. As anticipated, the Li/Co codoped P2-type oxide exhibits the absence of P2 - O2 phase transformation and Na+/vacancy disordering, which gives rise to an outstanding cycling stability (86.7% capacity retention within 100 cycles at 0.1C) and high-rate capability (reversible capacity of 109 mAh g-1 even at 10C). In addition, the full-cells composed of the codoped P2-type positive and hard carbon negative show high energy-density, good lifespan and high-rate property. This proposed cationic codoping provides an effective and scalable tactics for modulating the structural properties of high-voltage P2-type cathodes for advanced SIBs.

Role of NADPH Oxidase-Induced Hypoxia-Induced Factor-1α Increase in Blood-Brain Barrier Disruption after 2-Hour Focal Ischemic Stroke in Rat.

We recently showed that inhibition of hypoxia-induced factor-1α (HIF-1α) decreased acute ischemic stroke-induced blood-brain barrier (BBB) damage. However, factors that induce the upregulation of HIF-1α expression remain unclear. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase played a critical role in reperfusion-induced BBB damage after stroke. However, the role of NADPH oxidase in BBB injury during the acute ischemia stage remains unclear. This study is aimed at investigating the role of NADPH oxidase in BBB injury and the expression of HIF-1α after acute ischemic stroke. A sutured middle cerebral artery occlusion (MCAO) model was used to mimic ischemic stroke in rats. Our results show that the inhibition of NADPH oxidase by apocynin can significantly reduce the BBB damage caused by 2 h ischemic stroke accompanied by reducing the degradation of tight junction protein occludin. In addition, treatment with apocynin significantly decreased the upregulation of HIF-1α induced by 2 h MCAO. More importantly, apocynin could also inhibit the MMP-2 upregulation. Of note, HIF-1α was not colocalized with a bigger blood vessel. Taken together, our results showed that inhibition of NADPH oxidase-mediated HIF-1α upregulation reduced BBB damage accompanied by downregulating MMP-2 expression and occludin degradation after 2 h ischemia stroke. These results explored the mechanism of BBB damage after acute ischemic stroke and may help reduce the associated cerebral hemorrhage transformation after thrombolysis and endovascular treatment after ischemic stroke.

Clemastine attenuates AD-like pathology in an AD model mouse via enhancing mTOR-mediated autophagy.

Alzheimer's disease (AD) is a neurodegenerative disorder with limited available drugs for treatment. Enhancing autophagy attenuates AD pathology in various AD model mice. Thus, development of potential drugs which enhance autophagy may bring beneficial effects in AD therapy. In the present study, we show clemastine, a first-generation histamine H1R antagonist and being originally marketed for the treatment of allergic rhinitis, ameliorates AD pathogenesis in APP/PS1 transgenic mice. Chronic treatment with clemastine orally reduced amyloid-ß (Aß) load, neuroinflammation and cognitive deficits of APP/PS1 transgenic mice. Clemastine decreases Aß generation via reducing the levels of BACE1, CTFs of APP. Mechanistically, clemastine enhances autophagy concomitant with a suppression of mTOR signaling. Therefore, we propose that clemastine attenuates AD pathology via enhancing mTOR-mediated autophagy.

Intranasal Transplantation of Human Neural Stem Cells Ameliorates Alzheimer's Disease-Like Pathology in a Mouse Model.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairments, which has no effective therapy. Stem cell transplantation shows great potential in the therapy of various disease. However, the application of stem cell therapy in neurological disorders, especially the ones with a long-term disease course such as AD, is limited by the delivery approach due to the presence of the brain blood barrier. So far, the most commonly used delivery approach in the therapy of neurological disorders with stem cells in preclinical and clinical studies are intracranial injection and intrathecal injection, both of which are invasive. In the present study, we use repetitive intranasal delivery of human neural stem cells (hNSCs) to the brains of APP/PS1 transgenic mice to investigate the effect of hNSCs on the pathology of AD. The results indicate that the intranasally transplanted hNSCs survive and exhibit extensive migration and higher neuronal differentiation, with a relatively limited glial differentiation. A proportion of intranasally transplanted hNSCs differentiate to cholinergic neurons, which rescue cholinergic dysfunction in APP/PS1 mice. In addition, intranasal transplantation of hNSCs attenuates ß-amyloid accumulation by upregulating the expression of ß-amyloid degrading enzymes, insulin-degrading enzymes, and neprilysin. Moreover, intranasal transplantation of hNSCs ameliorates other AD-like pathology including neuroinflammation, cholinergic dysfunction, and pericytic and synaptic loss, while enhancing adult hippocampal neurogenesis, eventually rescuing the cognitive deficits of APP/PS1 transgenic mice. Thus, our findings highlight that intranasal transplantation of hNSCs benefits cognition through multiple mechanisms, and exhibit the great potential of intranasal administration of stem cells as a non-invasive therapeutic strategy for AD.

Engrafted primary type-2 astrocytes improve the recovery of the nigrostriatal pathway in a rat model of Parkinson's disease.

Parkinson's disease (PD) is a disorder characterized by a progressive loss of the dopaminergic neurons in the substantia nigra and a depletion of the neurotransmitter dopamine in the striatum. Our published results indicate that fasciculation and elongation protein zeta-1 (FEZ1) plays a role in the astrocyte-mediated protection of dopamine neurons and regulation of the neuronal microenvironment during the progression of PD. In this study, we examined the effects of engrafted type-2 astrocytes (T2As) with high expression of FEZ1 on the improvement of the symptoms and functional reconstruction of PD rats. T2As were stereotactically transplanted into the striatum of rats with PD induced by 6-hydroxydopamine (6-OHDA). An examination of apomorphine (APO)-induced rotations was performed to evaluate dopamine neuron damage and motor functions. Remarkably, the grafted cells survived in the lesion environment for six weeks or longer after implantation. In addition, the transplantation of T2As decrease the average velocity and the duration time of the APO-induced rotations, and increase the actuation time, as measured in the rotation behavioural tests. In the substantia nigra, the transplantation of T2As reduced the PD-induced GFAP, TH and FEZ1 downregulation. The grafted cells exclusively migrated to other regions near the injection site in the striatum and differentiated into GFAP+ astrocytes or TH+ neurons. Furthermore, by detecting monoamine neurotransmitters through high-performance liquid chromatography, we found that the nigrostriatal pathway had been repaired to some extent. Taken together, these results suggest that engrafted T2As with high expression of FEZ1 improved the symptoms and functional reconstruction of PD rats, providing a theoretical basis for FEZ1 as a potential target and engraftment of T2As as a therapeutic strategy in the treatment of PD.

D1 receptor-mediated endogenous tPA upregulation contributes to blood-brain barrier injury after acute ischaemic stroke.

Blood-brain barrier (BBB) integrity injury within the thrombolytic time window is becoming a critical target to reduce haemorrhage transformation (HT). We have previously reported that BBB damage was initially damaged in non-infarcted striatum after acute ischaemia stroke. However, the underlying mechanism is not clear. Since acute ischaemic stroke could induce a significant increase of dopamine release in striatum, in current study, our aim is to investigate the role of dopamine receptor signal pathway in BBB integrity injury after acute ischaemia using rat middle cerebral artery occlusion model. Our data showed that 2-h ischaemia induced a significant increase of endogenous tissue plasminogen activator (tPA) in BBB injury area and intra-striatum infusion of tPA inhibitor neuroserpin, significantly alleviated 2-h ischaemia-induced BBB injury. In addition, intra-striatum infusion of D1 receptor antagonist SCH23390 significantly decreased ischaemia-induced upregulation of endogenous tPA, accompanied by decrease of BBB injury and occludin degradation. More important, inhibition of hypoxia-inducible factor-1 alpha with inhibitor YC-1 significantly decreased 2-h ischaemia-induced endogenous tPA upregulation and BBB injury. Taken together, our data demonstrate that acute ischaemia disrupted BBB through activation of endogenous tPA via HIF-1α upregulation, thus representing a new therapeutic target for protecting BBB after acute ischaemic stroke.