Tau induces inflammasome activation and microgliosis through acetylating NLRP3.

BACKGROUND: Alzheimer's disease (AD) and related Tauopathies are characterised by the pathologically hyperphosphorylated and aggregated microtubule-associated protein Tau, which is accompanied by neuroinflammation mediated by activated microglia. However, the role of Tau pathology in microglia activation or their causal relationship remains largely elusive. METHODS: The levels of nucleotide-binding oligomerisation domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) acetylation and inflammasome activation in multiple cell models with Tau proteins treatment, transgenic mice with Tauopathy, and AD patients were measured by Western blotting and enzyme-linked immunosorbent assay. In addition, the acetyltransferase activity of Tau and NLRP3 acetylation sites were confirmed using the test-tube acetylation assay, co-immunoprecipitation, immunofluorescence (IF) staining, mass spectrometry and molecular docking. The Tau-overexpressing mouse model was established by overexpression of human Tau proteins in mouse hippocampal CA1 neurons through the adeno-associated virus injection. The cognitive functions of Tau-overexpressing mice were assessed in various behavioural tests, and microglia activation was analysed by Iba-1 IF staining and [18F]-DPA-714 positron emission tomography/computed tomography imaging. A peptide that blocks the interaction between Tau and NLRP3 was synthesised to determine the in vitro and in vivo effects of Tau-NLRP3 interaction blockade on NLRP3 acetylation, inflammasome activation, microglia activation and cognitive function. RESULTS: Excessively elevated NLRP3 acetylation and inflammasome activation were observed in 3xTg-AD mice, microtubule-associated protein Tau P301S (PS19) mice and AD patients. It was further confirmed that mimics of 'early' phosphorylated-Tau proteins which increase at the initial stage of diseases with Tauopathy, including TauT181E, TauS199E, TauT217E and TauS262E, significantly promoted Tau-K18 domain acetyltransferase activity-dependent NLRP3 acetylation and inflammasome activation in HEK293T and BV-2 microglial cells. In addition, Tau protein could directly acetylate NLRP3 at the K21, K22 and K24 sites at its PYD domain and thereby induce inflammasome activation in vitro. Overexpression of human Tau proteins in mouse hippocampal CA1 neurons resulted in impaired cognitive function, Tau transmission to microglia and microgliosis with NLRP3 acetylation and inflammasome activation. As a targeted intervention, competitive binding of a designed Tau-NLRP3-binding blocking (TNB) peptide to block the interaction of Tau protein with NLRP3 inhibited the NLRP3 acetylation and downstream inflammasome activation in microglia, thereby alleviating microglia activation and cognitive impairment in mice. CONCLUSIONS: In conclusion, our findings provide evidence for a novel role of Tau in the regulation of microglia activation through acetylating NLRP3, which has potential implications for early intervention and personalised treatment of AD and related Tauopathies.

Gypenoside IX restores Akt/GSK-3ß pathway and alleviates Alzheimer's disease-like neuropathology and cognitive deficits.

The main pathological changes of Alzheimer's disease (AD), a progressive neurodegenerative disorder, include senile plaque (deposited by amyloid beta), neurofibrillary tangle (formed by paired helical filaments composed of hyperphosphorylated tau), and massive loss of neurons. Currently there is a lack of ideal drugs to halt AD progression. Gypenosides (GPs), a kind of natural product, possesses potential therapeutic effects for neurodegenerative diseases, including AD. However, the specific role and mechanism of GPs for AD remain unclear. In the current study, we used staurosporine (STP), an inducer of apoptosis and causing tau hyperphosphorylation, to mimic AD models, and explored the role and mechanism of Gypenoside IX (one of the extracts of Gynostemma, GP for short name in our experiments) in STP treated primary hippocampal neurons and rats. We found STP not only increased apoptosis and tau hyperphosphorylation, but also significantly increased Aß production, resulting in synaptic dysfunction and cognitive decline in mimic AD models by STP. GP was found to rescue apoptosis and cognitive impairments caused by STP treatment. Moreover, GP recovered the decreased synaptic proteins PSD95, Synaptophysin and GluR2, and blocked dendritic spine loss. Interestingly, GP decreased the STP induced tau hyperphosphorylation at different sites including S-199, S-202, T-205, T-231, S-262, S-396, and S-404, and at the same time decreased Aß production through down-regulation of BACE1 and PS1. These effects in STP treated primary hippocampal neurons and rats were accompanied with a restoration of AKT/GSK-3ß signaling axis with GP treatment, supporting that dysregulation of AKT/GSK-3ß pathway might be involved in STP related AD pathogenesis. The results from our research proved that GP might be a potential candidate compound to reduce neuronal damage and prevent the cognitive decline in AD.

Microglia activation mediates circadian rhythm disruption-induced cognitive impairment in mice.

Alzheimer's disease (AD) is the leading cause of dementia and there are no effective treatments for this disease currently. Circadian rhythm disruption (CRD) is a hallmark of modern society that appears to be on the rise. It is well reported that AD is associated with disrupted circadian functioning and CRD can impair cognitive function. However, the cellular mechanisms underlying CRD-associated cognitive decline remain elusive. In this study, we investigated whether microglia are involved in CRD-induced cognitive decline. We established experimental 'jet lag' (phase delay of the light/dark cycles)-induced CRD mouse model and observed significant impairment of spatial learning and memory function in these mice. In the brain, CRD resulted in neuroinflammation, which was characterized by microglia activation and increased pro-inflammatory cytokine production, impairments in neurogenesis and reduction of synaptic proteins in the hippocampus. Interestingly, elimination of microglia with the colony stimulating factor-1 receptor inhibitor PLX3397 prevented CRD-induced neuroinflammation, cognitive decline, impairment of neurogenesis and loss of synaptic proteins. These findings collectively suggest that microglia activation plays a key role in CRD-induced cognitive deficit most likely through neuroinflammation-mediated impairments in adult neurogenesis and synapses.

Newly Detected Transmission of blaKPC-2 by Outer Membrane Vesicles in Klebsiella Pneumoniae.

OBJECTIVE: The prevalence of carbapenem-resistant Klebsiella pneumoniae (CR-KP) is a global public health problem. It is mainly caused by the plasmid-carried carbapenemase gene. Outer membrane vesicles (OMVs) contain toxins and other factors involved in various biological processes, including ß-lactamase and antibiotic-resistance genes. This study aimed to reveal the transmission mechanism of OMV-mediated drug resistance of Klebsiella (K.) pneumoniae. METHODS: We selected CR-KP producing K. pneumoniae carbapenemase-2 (KPC-2) to study whether they can transfer resistance genes through OMVs. The OMVs of CR-KP were obtained by ultracentrifugation, and incubated with carbapenem-sensitive K. pneumoniae for 4 h. Finally, the carbapenem-sensitive K. pneumoniae was tested for the presence of blaKPC-2 resistance gene and its sensitivity to carbapenem antibiotics. RESULTS: The existence of OMVs was observed by the electron microscopy. The extracted OMVs had blaKPC-2 resistance gene. After incubation with OMVs, blaKPC-2 resistance gene was detected in sensitive K. pneumoniae, and it became resistant to imipenem and meropenem. CONCLUSION: This study demonstrated that OMVs isolated from KPC-2-producing CR-KP could deliver blaKPC-2 to sensitive K. pneumoniae, allowing the bacteria to produce carbapenemase, which may provide a novel target for innovative therapies in combination with conventional antibiotics for treating carbapenem-resistant Enterobacteriaceae.

Rifaximin protects against circadian rhythm disruption-induced cognitive impairment through preventing gut barrier damage and neuroinflammation.

Circadian rhythm disruption (CRD) is a potential risk factor for developing Alzheimer's disease (AD). However, the mechanistic link between CRD and AD is still not fully understood. CRD may lead to intestinal barrier impairment. Several studies in animals and humans suggest a connection between gut microbiota disturbance, intestinal barrier damage and neurodegenerative diseases. In this study, we investigated the effect of CRD on cognition in mice and explored the role of intestinal barrier and inflammatory responses in this process. CRD modulates the composition of gut microbiota, impairs intestinal barrier integrity, and induces both peripheral and central inflammation and cognitive impairment in mice. Rifaximin, a non-absorbable antibiotic which modulates the gut microbial composition and increases intestinal barrier integrity, effectively suppresses inflammatory responses, and rescues cognitive impairment induced by CRD. Furthermore, the impairment in hippocampal neurogenesis, tau hyperphosphorylation, and loss in synaptic proteins in CRD mice is also reversed by Rifaximin. These data identify that the impaired intestinal barrier integrity related to gut microbiota disturbance plays a key role in CRD-induced inflammatory responses and cognitive impairments in mice, and Rifaximin is effective in preventing CRD-induced cognitive deficit through protecting the gut barrier and ameliorating neuroinflammation.

Chk1 Inhibition Ameliorates Alzheimer's Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling.

Alzheimer's disease (AD) is the most common neurodegenerative disease with limited therapeutic strategies. Cell cycle checkpoint protein kinase 1 (Chk1) is a Ser/Thr protein kinase which is activated in response to DNA damage, the latter which is an early event in AD. However, whether DNA damage-induced Chk1 activation participates in the development of AD and Chk1 inhibition ameliorates AD-like pathogenesis remain unclarified. Here, we demonstrate that Chk1 activity and the levels of protein phosphatase 2A (PP2A) inhibitory protein CIP2A are elevated in AD human brains, APP/PS1 transgenic mice, and primary neurons with Aß treatment. Chk1 overexpression induces CIP2A upregulation, PP2A inhibition, tau and APP hyperphosphorylation, synaptic impairments, and cognitive memory deficit in mice. Moreover, Chk1 inhibitor (GDC0575) effectively increases PP2A activity, decreases tau phosphorylation, and inhibits Aß overproduction in AD cell models. GDC0575 also reverses AD-like cognitive deficits and prevents neuron loss and synaptic impairments in APP/PS1 mice. In conclusion, our study uncovers a mechanism by which DNA damage-induced Chk1 activation promotes CIP2A-mediated tau and APP hyperphosphorylation and cognitive dysfunction in Alzheimer's disease and highlights the therapeutic potential of Chk1 inhibitors in AD.

Highly Selective Tandem Electroreduction of CO2 to Ethylene over Atomically Isolated Nickel-Nitrogen Site/Copper Nanoparticle Catalysts.

Herein, an effective tandem catalysis strategy is developed to improve the selectivity of the CO2 RR towards C2 H4 by multiple distinct catalytic sites in local vicinity. An earth-abundant elements-based tandem electrocatalyst PTF(Ni)/Cu is constructed by uniformly dispersing Cu nanoparticles (NPs) on the porphyrinic triazine framework anchored with atomically isolated nickel-nitrogen sites (PTF(Ni)) for the enhanced CO2 RR to produce C2 H4 . The Faradaic efficiency of C2 H4 reaches 57.3 % at -1.1 V versus the reversible hydrogen electrode (RHE), which is about 6 times higher than the non-tandem catalyst PTF/Cu, which produces CH4 as the major carbon product. The operando infrared spectroscopy and theoretic density functional theory (DFT) calculations reveal that the local high concentration of CO generated by PTF(Ni) sites can facilitate the C-C coupling to form C2 H4 on the nearby Cu NP sites. The work offers an effective avenue to design electrocatalysts for the highly selective CO2 RR to produce multicarbon products via a tandem route.

Alterations of fatty acid composition and metabolism in APP/PS1 transgenic mice.

Accumulating evidence suggests that abnormal fatty acid composition is related to the development of Alzheimer's disease (AD). However, there is no consistency in the fatty acid profile and metabolism associated with AD pathogenesis. This study aims to define the characteristics of fatty acid composition and metabolism in AD. Using 6-month-old APP/PS1 transgenic mice with wild-type mice as a control, we examined the serum lipids, brain fatty acid composition, and the expression levels of various genes involved in liver fatty acid ß-oxidation. The results of our study demonstrate that APP/PS1 mice present decreased serum free fatty acids, altered brain fatty acid profiles, and minimal change in liver fatty acid ß-oxidation. Our results suggest that abnormal fatty acid compositions and contents may play potential roles in AD progression. This study provides further evidence for the metabolic basis of AD pathogenesis.

FoxO1 overexpression reduces Aß production and tau phosphorylation in vitro.

Forkhead box O1 (FoxO1), a key molecule in the regulation of cell growth, differentiation and metabolism, is an important transcription factor. However, the effect of FoxO1 on Alzheimer's disease (AD) needs further investigation. In this study, we aimed to explore the function and mechanism of FoxO1 in amyloid-ß (Aß) production and tau phosphorylation in AD. First, compared with the age matched wild-type (WT) mice, we showed that FoxO1 protein levels were reduced in the cortices but nearly unchanged in the hippocampi of 6-month-old APPswe/PSEN1dE9 transgenic mice expressing Swedish APP and Presenilin1 delta exon 9 mutations (APP/PS1 mice). Then, we found that overexpression of FoxO1 significantly attenuated Aß production through inhibiting the amyloidogenic processing of ß-amyloid precursor protein (APP), mediated by the key enzymes BACE1 and PS1, in N2a/APPsw cells. Furthermore, in FoxO1-overexpressing HEK293/Tau cells, the decreased levels of tau phosphorylation at selective sites (S262 and T231) were accompanied by increasing the expression of p-GSK-3ß (S9), and reducing p-ERK. In contrast, the total tau (Tau-5), non-phosphorylated tau (Tau-1), p-Tau (S404), CDK5 and PP2A levels remained unchanged. These findings indicate that FoxO1 is related to AD and suggest FoxO1 as a therapeutic target for AD that reduces the levels of both Aß expression and tau phosphorylation.

Encapsulating polyaniline within porous MIL-101 for high-performance corrosion protection.

The metal corrosion possesses a serious threat to the safety and loss of property. The anticorrosion study on metal-organic frameworks (MOFs) remains rarely reported. Therefore, it is desirable to build MOFs-based anticorrosion coating with long-term corrosion resistance. Herein, we prepared a novel MOF-polymer anticorrosion composite PANI@MIL-101 by encapsulating polyaniline (PANI) within the pores of MIL-101 with in-situ polymerization of aniline monomer. The N2 adsorption-desorption and transmission electron microscopy (TEM) of PANI@MIL-101 illustrate that PANI is successfully encapsulated in the pores of MIL-101 with in-situ polymerization. PANI@MIL-101 was dispersed in epoxy resin (EP) to prepare anti-corrosive coatings. The Tafel potentiodynamic polarization measurements and electrochemical impedance spectroscopy show that PANI@MIL-101/EP coating system has superior corrosion protection with the lowest icorr value and the highest |Z|0.01 value compared with MIL-101/EP coating, PANI/EP coating and EP coating. A possible anticorrosion mechanism of PANI@MIL-101 was discussed. This work reveals that MOF-polymer composite materials are superb candidates for high-performance corrosion protection.

Erratum to: Protein Phosphatase 2A as a Drug Target in the Treatment of Cancer and Alzheimer's Disease.

The article "Protein Phosphatase 2A as a Drug Target in the Treatment of Cancer and Alzheimer's Disease", written by Hui WEI, Hui-liang ZHANG, Jia-zhao XIE, Dong-li MENG, Xiao-chuan WANG, Dan KE, Ji ZENG, Rong LIU, was originally published electronically on the publisher's internet portal on 13 March 2020 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed to © The Author(s) 2020 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The original article has been corrected.Corresponding authors: Dan KE, E-mail: kedan@hust.edu.cn; Ji ZENG, E-mail: whzjmicro@163.com.

Protein Phosphatase 2A as a Drug Target in the Treatment of Cancer and Alzheimer's Disease.

Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase which participates in the regulation of multiple cellular processes. As a confirmed tumor suppressor, PP2A activity is downregulated in tumors and its re-activation can induce apoptosis of cancer cells. In the brains of Alzheimer's disease (AD) patients, decreased PP2A activity also plays a key role in promoting tau hyperphosphorylation and Aß generation. In this review, we discussed compounds aiming at modulating PP2A activity in the treatment of cancer or AD. The upstream factors that inactivate PP2A in diseases have not been fully elucidated and further studies are needed. It will help for the refinement and development of novel and clinically tractable PP2A-targeted compounds or therapies for the treatment of tumor and AD.

Agar-reduced graphene oxide selectively adsorbs organic dyes and strengthens double-network hydrogels.

A straightforward and environmentally friendly method for synthesizing agar-reduced graphene oxide (ArGO) was devised. The topological features and emergent physical properties displayed by the novel carbon material were controlled by varying its water content. Dehydrated films of ArGO were found to be stable in water due to the π-π stacking interactions that formed between the aromatic components of its constituent sheets. In contrast, porous variants of ArGO afforded hydrogels that exhibited high swelling capacities. The intrinsic mechanical strength, elasticity and chemical stability of the hydrogels were further enhanced through adaption into double-network analogues. Such hydrogels, which were prepared using a facile and efficient one-pot methodology, exhibited a high fracture stress upon compression, and retained their shape in basic aqueous environments. These features can be expected to enable water purification and tissue engineering applications, among others.

Migration-Prevention Strategy to Fabricate Single-Atom Fe Implanted N-Doped Porous Carbons for Efficient Oxygen Reduction.

It is highly desired but challenging to achieve highly active single-atom Fe sites from iron-based metal-organic frameworks (MOFs) for efficient oxygen reduction reaction (ORR) due to the easy aggregation of iron species and formation of the inactive Fe-based particles during pyrolysis. Herein, a facile migration-prevention strategy is developed involving the incorporation of polyaniline (PANI) into the pores of iron porphyrinic-based MOF PCN-224(Fe) and followed by pyrolysis to obtain the single-atom Fe implanted N-doped porous carbons material PANI@PCN-224(Fe)-900. The introduced PANI inside the pores of PCN-224(Fe) not only served as protective fences to prevent the aggregation of the iron species during thermal annealing, but also acted as nitrogen sources to increase the nitrogen content and form Fe-Nx-C active sites. Compared with the pristine PCN-224(Fe) derived carbonization sample containing Fe-based particles, the carbonaceous material PANI@PCN-224(Fe)-900 without inactive Fe-based particles exhibited superb ORR electrocatalytic activity with a more positive half-wave potential, significantly improved stability in both alkaline media, and more challenging acidic condition. The migration-prevention strategy provides a new way to fabricate atomically dispersed metal active sites via pyrolysis approach for promoting catalysis.

Unraveling the relationship between the morphologies of metal-organic frameworks and the properties of their derived carbon materials.

Metal-organic framework (MOF) derived carbon materials are promising for energy storage and conversion as they could inherit the advantages of MOF precursors, such as high porosity, large surface area and uniform heteroatom doping. Although the morphologies of MOF precursors have a significant effect on the properties of the resulting materials, up to now, there has been no systematic study on the relationship of the morphologies of MOFs and the properties of their pyrolized carbonaceous materials. Herein, three isomorphous imidazolate-based ZIF-7 materials with different morphologies (sphere, polyhedron and rod shape) have been selected as precursors and carbonized to obtain porous N-doped carbon materials with a tunable morphology, pore features and surface areas. The spherical precursor ZIF-7-S with an average size of 45 nm was cross-linked to form carbon networks during pyrolysis, while the rod shape of ZIF-7-R (0.6 µm in diameter and 3 µm in length) was well retained in the NC-R-800 material. NC-D-800 derived from polyhedral ZIF-7-D (125 nm) was constructed by partially interlinked particles and interparticle mesopores were formed. NC-D-800 has the highest Brunauer-Emmett-Teller (BET) surface area of 538 m2 g-1 of the three carbon materials. Moreover, NC-D-800 shows superiority over NC-S-800 and NC-R-800 in the oxygen reduction reaction. This work discloses that the morphologies of MOF precursors could indeed affect the morphologies, and physical and catalytic properties of their corresponding carbon materials.

Controlled Growth of Well-Defined Conjugated Polymers from the Surfaces of Multiwalled Carbon Nanotubes: Photoresponse Enhancement via Charge Separation.

The installation of heterojunctions on the surfaces of carbon nanotubes (CNTs) is an effective method for promoting the charge separation processes needed for CNT-based electronics and optoelectronics applications. Conjugated polymers are proven state-of-the-art candidates for modifying the surfaces of CNTs. However, all previous attempts to incorporate conjugated polymers to CNTs resulted in unordered interfaces. Herein we show that well-defined chains of regioregular poly(3-hexylthiophene) (P3HT) were successfully grown from the surfaces of multiwalled CNTs (MWNTs) using surface-initiated Kumada catalyst-transfer polycondensation. The polymerization was found to proceed in a controlled manner as chains of tunable lengths were prepared through variation of the initial monomer-to-initiator ratio. Moreover, it was determined that large-diameter MWNTs afforded highly ordered P3HT aggregates, which exhibited a markedly bathochromically shifted optical absorption due to a high grafting density induced planarization of the polymer chains. Using ultrafast spectroscopy, the heterojunctions formed between the MWNTs and P3HT were shown to effectively overcome the binding energy of excitons, leading to photoinduced electron transfer from P3HT to MWNTs. Finally, when used as prototype devices, the individual MWNT-g-P3HT core-shell structures exhibited excellent photoresponses under a low illumination density.

The enhanced photothermal effect of graphene/conjugated polymer composites: photoinduced energy transfer and applications in photocontrolled switches.

Composites prepared by grafting poly(3-hexylthiophene) (P3HT) onto the surfaces of reduced graphene oxide (RGO) (RGO-g-P3HT) exhibit an enhanced photothermal effect due to photoinduced energy transfer from P3HT to RGO. A remote photo-controlled electrical switch was prepared using RGO-g-P3HT as a photothermal layer.

Composite films of poly(3-hexylthiophene) grafted single-walled carbon nanotubes for electrochemical detection of metal ions.

In this study, we prepared electrochemically active films of poly(3-hexylthiophene) grafted single-walled carbon nanotubes (SWNT-g-P3HT) by using a modified vacuum-assisted deposition approach, in which a SWNT-g-P3HT composite layer of various thicknesses was deposited on the top of a thin SWNT layer. Measurement of the optical and electrical properties of the SWNT-g-P3HT composite films demonstrated that the thickness of the SWNT-g-P3HT composite films was controllable. The data of transmission electron microscope observation and Raman spectroscopy indicated that the covalent grafting of P3HT onto the surfaces of SWNTs resulted in intimate and stable connectivity between the two components in the SWNT-g-P3HT composite. Capitalizing on these unique features, we successfully developed a new class of electrochemical sensors that used the SWNT-g-P3HT composite films deposited on an indium-tin oxide substrate as an electrochemical electrode for detection of metal ions. Significantly, such a SWNT-g-P3HT composite electrode showed advantages in selective, quantitative, and more sensitive detection of Ag(+) ions.

Enhanced photoresponse of large-sized photoactive graphene composite films based on water-soluble conjugated polymers.

Composite films of chemically converted graphene (CCG) and water-soluble polythiophenes (P3TOPS and P3TOPA) were prepared by a LBL method using a suspension of negatively charged CCG-P3TOPS sheets and a solution of positively charged P3TOPA. The composite films show enhanced photoresponse due to photoinduced electron transfer from the polythiophenes to CCG.