Efficient exact exchange using Wannier functions and other related developments in planewave-pseudopotential implementation of RT-TDDFT.

The plane-wave pseudopotential (PW-PP) formalism is widely used for the first-principles electronic structure calculation of extended periodic systems. The PW-PP approach has also been adapted for real-time time-dependent density functional theory (RT-TDDFT) to investigate time-dependent electronic dynamical phenomena. In this work, we detail recent advances in the PW-PP formalism for RT-TDDFT, particularly how maximally localized Wannier functions (MLWFs) are used to accelerate simulations using the exact exchange. We also discuss several related developments, including an anti-Hermitian correction for the time-dependent MLWFs (TD-MLWFs) when a time-dependent electric field is applied, the refinement procedure for TD-MLWFs, comparison of the velocity and length gauge approaches for applying an electric field, and elimination of long-range electrostatic interaction, as well as usage of a complex absorbing potential for modeling isolated systems when using the PW-PP formalism.

Real-Time Time-Dependent Density Functional Theory for Simulating Nonequilibrium Electron Dynamics.

The explicit real-time propagation approach for time-dependent density functional theory (RT-TDDFT) has increasingly become a popular first-principles computational method for modeling various time-dependent electronic properties of complex chemical systems. In this Perspective, we provide a nontechnical discussion of how this first-principles simulation approach has been used to gain novel physical insights into nonequilibrium electron dynamics phenomena in recent years. Following a concise overview of the RT-TDDFT methodology from a practical standpoint, we discuss our recent studies on the electronic stopping of DNA in water and the Floquet topological phase as examples. Our discussion focuses on how RT-TDDFT simulations played a unique role in deriving new scientific understandings. We then discuss existing challenges and some new advances at the frontier of RT-TDDFT method development for studying increasingly complex dynamic phenomena and systems.

Theory of moment propagation for quantum dynamics in single-particle description.

We present a novel theoretical formulation for performing quantum dynamics in terms of moments within the single-particle description. By expressing the quantum dynamics in terms of increasing orders of moments, instead of single-particle wave functions as generally done in time-dependent density functional theory, we describe an approach for reducing the high computational cost of simulating the quantum dynamics. The equation of motion is given for the moments by deriving analytical expressions for the first-order and second-order time derivatives of the moments, and a numerical scheme is developed for performing quantum dynamics by expanding the moments in the Taylor series as done in classical molecular dynamics simulations. We propose a few numerical approaches using this theoretical formalism on a simple one-dimensional model system, for which an analytically exact solution can be derived. The application of the approaches to an anharmonic system is also discussed to illustrate their generality. We also discuss the use of an artificial neural network model to circumvent the numerical evaluation of the second-order time derivatives of the moments, as analogously done in the context of classical molecular dynamics simulations.

First-Principles Approach for Coupled Quantum Dynamics of Electrons and Protons in Heterogeneous Systems.

The coupled quantum dynamics of electrons and protons is ubiquitous in many dynamical processes involving light-matter interaction, such as solar energy conversion in chemical systems and photosynthesis. A first-principles description of such nuclear-electronic quantum dynamics requires not only the time-dependent treatment of nonequilibrium electron dynamics but also that of quantum protons. Quantum mechanical correlation between electrons and protons adds further complexity to such coupled dynamics. Here we extend real-time nuclear-electronic orbital time-dependent density functional theory (RT-NEO-TDDFT) to periodic systems and perform first-principles simulations of coupled quantum dynamics of electrons and protons in complex heterogeneous systems. The process studied is an electronically excited-state intramolecular proton transfer of o-hydroxybenzaldehyde in water and at a silicon (111) semiconductor-molecule interface. These simulations illustrate how environments such as hydrogen-bonding water molecules and an extended material surface impact the dynamical process on the atomistic level. Depending on how the molecule is chemisorbed on the surface, excited-state electron transfer from the molecule to the semiconductor surface can inhibit ultrafast proton transfer within the molecule. This Letter elucidates how heterogeneous environments influence the balance between the quantum mechanical proton transfer and excited electron dynamics. The periodic RT-NEO-TDDFT approach is applicable to a wide range of other photoinduced heterogeneous processes.

Molecular Control of Floquet Topological Phase in Non-adiabatic Thouless Pumping.

Non-adiabatic Thouless pumping of electrons is studied in the framework of topological Floquet engineering, particularly with a focus on how atomistic changes to chemical moieties control the emergence of the Floquet topological phase. We employ real-time time-dependent density functional theory to investigate the extent to which the topological invariant, the winding number, is impacted by molecular-level changes to trans-polyacetylene. In particular, several substitutions to trans-polyacetylene are studied to examine different effects on the electronic structure, including the mesomeric effect, inductive effect, and electron conjugation effect. Maximally localized Wannier functions are employed to relate the winding number to the valence bond description by expressing the topological pumping as the transport dynamics of the localized Wannier functions. By further exploiting the gauge invariance of the quantum dynamics in terms of the minimal particle-hole excitations, the topological pumping of electrons can be also represented as a cyclic transition among the bonding and antibonding orbitals. Having connected the topological invariant to the chemical concepts, we demonstrate molecular-level control of the emergence of the Floquet topological phase, presenting an exciting opportunity for the intuitive engineering of molecular systems with such an exotic topological phase.

The Gut Microbiota-Brain Axis: Potential Mechanism of Drug Addiction.

As a chronic encephalopathy, drug addiction is responsible for millions of deaths per year around the world. The gut microbiome is a crucial component of the human microbiome. Through dynamic bidirectional communication along the 'gut-brain axis,' gut bacteria cooperate with their hosts to regulate the development and function of the immune, metabolic, and nervous systems. These processes may affect human health because some brain diseases are related to the composition of gut bacteria, and disruptions in microbial communities have been implicated in neurological disorders. We review the compositional and functional diversity of the gut microbiome in drug addiction. We discuss intricate and crucial connections between the gut microbiota and the brain involving multiple biological systems and possible contributions by the gut microbiota to neurological disorders. Finally, the treatment of probiotics and fecal transplantation was summarized. This was done to further understand the role of intestinal microecology in the pathogenesis of drug addiction and to explore new methods for the treatment of drug addiction.

A novel gene therapy for methamphetamine- induced cognitive disorder with a hyper-acidified fusion variant of DnaJB1.

Methamphetamine (MA) is spread worldwide and is a highly addictive psychostimulant that can induce neurodegeneration and cognitive disorder, which lacks effective treatments. We and other researchers have found that the crucial member of Hsp70 chaperone machinery, DnaJ, is liable to be co-aggregated with aberrant proteins, which has been confirmed a risk factor to promote neurodegeneration. In the current study, we demonstrated that tailing with a hyper-acidic fusion partner, tua2, human DnaJB1 could resist the formation of toxic mutant Tau aggregates both in prokaryote and eukaryote models. We found that aberrant Tau aggregates could deplete the antioxidant enzyme pool and disturb Hsp70 molecular chaperone system by co-aggregating with the principal members of these systems. Stability-enhanced DnaJB1-tua2 could stop the chain reaction of Tau aggregates as well as maintain redox balance and protein homeostasis. With an MA-induced cognitive disorder mouse model, we found that the cognitive disorder of MA mice was rescued and the overactivated inflammatory response was relieved by the expression of DnaJB1-tua2 in the hippocampus. Furthermore, the Tau neurofibrillary tangles and apoptotic neurons were diminished with the escorting of DnaJB1-tua2. These findings demonstrate that delivering DnaJB1-tua2 in hippocampus may have a therapeutic potential in the treatment of MA-induced cognitive disorder.

Ubiquitin­specific protease 8 ameliorates lipopolysaccharide­induced spleen injury via suppression of NF­κB and MAPK signaling pathways.

In human immunity, the spleen is a major organ, being central to humoral and cellular immunity. In vitro and in vivo, inflammation is regulated by ubiquitin­specific protease 8 (USP8); however, to the best of our knowledge, the effect of USP8 on spleen injury remains unknown. The present study aimed to investigate the protection offered by USP8 against spleen injury in lipopolysaccharide (LPS)­induced mice via attenuation of inflammation. A total of 119 C57BL/6J mice were placed into the following groups: Control group, saline group, LPS group, USP8 group, USP8 + LPS group and negative control (NC) + LPS group. A USP8 lentivirus was injected into mice at 1x108 TU/ml intracerebroventricularly for 7 days before LPS was administered via intraperitoneal injection at 750 µg/kg. From each group, serum and spleen samples were collected for analysis. Histological imaging was used to examine the spleen structure. Western blotting was used to detect the expression levels of proteins associated with the mitogen­activated protein kinase (MAPK) and nuclear factor (NF)­κB signaling pathways. Pro­inflammatory cytokines were detected using enzyme­linked immunosorbent assays. Compared with that in the saline, control and USP8 + LPS groups, the spleen volume in the LPS group was markedly increased, and the width of the splenic cord and sinus exhibited morphological damage in the LPS group. Compared with that in the saline, control and USP8 + LPS groups, the protein expression levels of USP8 in the spleen were decreased in the LPS group. Furthermore, the production of LPS­induced pro­inflammatory cytokines (e.g., interleukin­1ß and tumor necrosis factor­α) was reduced in serum and spleen homogenates by USP8. Related inflammatory pathways, including the NF­κB and MAPK pathways, were downregulated in the USP8 + LPS group compared with those in the LPS group. In conclusion, the anti­inflammatory effect of USP8 on LPS­induced spleen injury may be mediated by the inhibition of MAPK and NF­κB signaling pathways.

Targeted brain delivery of RVG29-modified rifampicin-loaded nanoparticles for Alzheimer's disease treatment and diagnosis.

Alzheimer's disease (AD) is an aging-related neurodegenerative disease. The main pathological features of AD are ß-amyloid protein (Aß) deposition and tau protein hyperphosphorylation. Currently, there are no effective drugs for the etiological treatment of AD. Rifampicin (RIF) is a semi-synthetic broad-spectrum antibiotic with anti-ß-amyloid deposition, anti-inflammatory, anti-apoptosis, and neuroprotective effects, but its application in AD treatment has been limited for its strong hydrophobicity, high toxicity, short half-life, low bioavailability, and blood-brain barrier hindrance. We designed a novel brain-targeted and MRI-characteristic nanomedicine via loading rabies virus protein 29 (RVG29), rifampicin, and Gd on poly (l-lactide) nanoparticles (RIF@PLA-PEG-Gd/Mal-RVG29). The cytotoxicity assay demonstrated that RIF@PLA-PEG-Gd/Mal-RVG29 had favorable biocompatibility and security. Fluorescence imaging in vivo showed that PLA-PEG-Gd/Mal-RVG29 could deliver rifampicin into the brain by enhancing cellular uptake and brain targeting performance, leading to improvement of the bioavailability of rifampicin. In in vivo study, RIF@PLA-PEG-Gd/Mal-RVG29 improved the spatial learning and memory capability of APP/PS1 mice in the Morris water maze, as compared to rifampicin. Immunofluorescence, TEM, immunoblotting, and H&E staining revealed that RIF@PLA-PEG-Gd/Mal-RVG29 reduced Aß deposition in hippocampal and cortex of APP/PS1 mice, improved the damage of synaptic ultrastructure, increased the expression level of PSD95 and SYP, as well as reduced the necrosis of neurons. These findings suggest that RIF@PLA-PEG-Gd/Mal-RVG29 may be an effective strategy for the treatment of AD.

Exercise modulates central and peripheral inflammatory responses and ameliorates methamphetamine-induced anxiety-like symptoms in mice.

Anxiety-like symptoms are common symptoms of methamphetamine (METH) users, especially in the acute withdrawal period, which is an important factor for the high relapse rate during METH acute withdrawal. Exercise has been demonstrated to relieve anxiety-like symptoms during METH withdrawal, but the underlying mechanisms of this anti-anxiety effect are still unclear. Activated microglia and abnormal neuroinflammation play an important role in the pathogenesis of anxiety-like symptoms after METH withdrawal. Moreover, peripheral immune factors were also significantly associated with anxiety symptoms. However, the effects of treadmill exercise on microglial function and neuroinflammation in the striatum and hippocampus during acute METH withdrawal have not been reported. In the current study, we found severe peripheral immune dysfunction in METH users during acute withdrawal, which may in part contribute to anxiety symptoms during METH acute withdrawal. We also showed that 2 weeks of METH exposure induced anxiety-like symptoms in the acute withdrawal period. Additionally, METH exposure resulted in increased microglial activation and proinflammatory cytokines released in the mouse striatum and hippocampus during acute withdrawal. We next evaluated the effects of treadmill exercise in countering anxiety-like symptoms induced by METH acute withdrawal. The results showed that anxiety-like symptoms induced by acute METH withdrawal were attenuated by coadministration of treadmill exercise. In addition, treadmill exercise counteracted METH-induced microglial activation in the mouse striatum and various subregions of the hippocampus. Furthermore, treadmill exercise also reversed the increase in proinflammatory cytokines induced by acute METH withdrawal in the mouse striatum, hippocampus and serum. Our findings suggest that the anti-anxiety effect of treadmill exercise may be mediated by reducing microglial activation and regulating central and peripheral inflammatory responses.

A Polymeric Strategy Empowering Vascular Cell Selectivity and Potential Application Superior to Extracellular Matrix Peptides.

Endothelialization of vascular implants plays a vital role in maintaining the long-term vascular patency. In situ endothelialization and re-endothelialization is generally achieved by selectively promoting endothelial cell (EC) adhesion and, meanwhile, suppressing smooth muscle cell (SMC) adhesion. Currently, such EC versus SMC selectivity is achieved and extensively used in vascular-related biomaterials utilizing extracellular-matrix-derived EC-selective peptides, dominantly REDV and YIGSR. Nevertheless, the application of EC-selective peptides is limited due to their easy proteolysis, time-consuming synthesis, and expensiveness. To address these limitations, a polymeric strategy in designing and finding EC-selective biomaterials using amphiphilic ß-peptide polymers by tuning serum protein adsorption is reported. The optimal ß-peptide polymer displays EC versus SMC selectivity even superior to EC-selective REDV peptide regarding cell adhesion, proliferation, and migration of ECs versus SMCs. Study of the mechanism indicates that surface adsorption of bovine serum albumin, an abundant and anti-adhesive serum protein, plays a critical role in the ECs versus SMCs selectivity of ß-peptide polymer. In addition, surface modification of the optimal ß-peptide polymer effectively promotes the endothelialization of vascular implants and inhibits intimal hyperplasia. This study provides an alternative strategy in designing and finding EC-selective biomaterials, implying great potential in the vascular-related biomaterial study and application.

Nuclear-electronic orbital approach to quantization of protons in periodic electronic structure calculations.

The nuclear-electronic orbital (NEO) method is a well-established approach for treating nuclei quantum mechanically in molecular systems beyond the usual Born-Oppenheimer approximation. In this work, we present a strategy to implement the NEO method for periodic electronic structure calculations, particularly focused on multicomponent density functional theory (DFT). The NEO-DFT method is implemented in an all-electron electronic structure code, FHI-aims, using a combination of analytical and numerical integration techniques as well as a resolution of the identity scheme to enhance computational efficiency. After validating this implementation, proof-of-concept applications are presented to illustrate the effects of quantized protons on the physical properties of extended systems, such as two-dimensional materials and liquid-semiconductor interfaces. Specifically, periodic NEO-DFT calculations are performed for a trans-polyacetylene chain, a hydrogen boride sheet, and a titanium oxide-water interface. The zero-point energy effects of the protons as well as electron-proton correlation are shown to noticeably impact the density of states and band structures for these systems. These developments provide a foundation for the application of multicomponent DFT to a wide range of other extended condensed matter systems.

Long-term exercise at different intensities can reduce the inflammatory response in the brains of methamphetamine-treated mice.

Methamphetamine (METH) is a highly addictive psychoactive drug that is used worldwide. Various approaches have been used to address METH dependence, but many of them have little effect. Previous studies have shown that exercise on a treadmill could reduce METH dependence in mice, but the intensity and duration of exercise that was needed to be effective was unknown. This study investigated the effects of low- and medium-intensity treadmill exercise on methamphetamine reward in male mice via conditioned place preference (CPP) training, and the levels of the inflammatory factors IL-1ß, IL-6 and TNF-α in three brain regions (cerebral cortex, hippocampus and striatum) were determined. The results showed that long-term medium-intensity exercise reduced the effects of methamphetamine on inflammation markers in the brain and CPP scores. In addition, long-term medium-intensity exercise decreased IL-1ß concentrations in the cerebral cortex and hippocampus, reduced IL-6 concentrations in the striatum, and reduced TNF-α concentrations in the cerebral cortex, hippocampus, and striatum in methamphetamine-treated mice; low-intensity exercise was less effective. The results indicated that long-term medium-intensity exercise could reduce concentrations of methamphetamine-induced encephalitis factors in male mice, while low-intensity exercise was less effective in alleviating dependence and inflammatory responses. It is suggested that exercise intensity is an important factor affecting the dependence level and inflammatory responses in the brain in mice administered methamphetamine.

Simulating electronic excitation and dynamics with real-time propagation approach to TDDFT within plane-wave pseudopotential formulation.

We give a perspective on simulating electronic excitation and dynamics using the real-time propagation approach to time-dependent density functional theory (RT-TDDFT) in the plane-wave pseudopotential formulation. RT-TDDFT is implemented in various numerical formalisms in recent years, and its practical application often dictates the most appropriate implementation of the theory. We discuss recent developments and challenges, emphasizing numerical aspects of studying real systems. Several applications of RT-TDDFT simulation are discussed to highlight how the approach is used to study interesting electronic excitation and dynamics phenomena in recent years.

First-Principles Demonstration of Nonadiabatic Thouless Pumping of Electrons in a Molecular System.

We demonstrate nonadiabatic Thouless pumping of electrons in trans-polyacetylene in the framework of Floquet engineering using first-principles theory. We identify the regimes in which the quantized pump is operative with respect to the driving electric field for a time-dependent Hamiltonian. By employing the time-dependent maximally localized Wannier functions in real-time time-dependent density functional theory simulation, we connect the winding number, a topological invariant, to a molecular-level understanding of the quantized pumping. While the pumping dynamics constitutes the opposing movement of the Wannier functions that represent both double and single bonds, the resulting current is unidirectional due to the greater number of double-bond electrons. Using a gauge-invariant formulation called dynamical transition orbitals, an alternative viewpoint on the nonequilibrium dynamics is obtained in terms of the particle-hole excitation. A single time-dependent transition orbital is found to be largely responsible for the observed quantized pumping. In this representation, the pumping dynamics manifests itself in the dynamics of this single orbital as it undergoes changes from its π bonding orbital character at equilibrium to acquiring resonance and antibonding character in the driving cycle. The work demonstrates the Floquet engineering of the nonadiabatic topological state in an extended molecular system, paving the way for experimental realization of the new quantum material phase.

Dl-butylphthalide inhibits rotenone-induced oxidative stress in microglia via regulation of the Keap1/Nrf2/HO-1 signaling pathway.

Activated microglia are a source of superoxide which often increases oxidative stress in the brain microenvironment, increase production of reactive oxygen species (ROS) and directly or indirectly lead to dopaminergic neuronal death in the substantia nigra. Thus superoxide contributes to the pathogenesis of Parkinson's disease (PD). Evidence suggests that mitochondria are the main source of ROS, which cause oxidative stress in cells. Levels of ROS are thus associated with the function of the mitochondrial complex. Therefore, protecting the mitochondrial function of microglia is important for the treatment of PD. Dl-butylphthalide (NBP), a compound isolated from Chinese celery seeds, has been approved by the China Food and Drug Administration for the treatment of acute ischemic stroke. Recently, NBP demonstrated therapeutic potential for PD. However, the mechanism underlying its neuroprotective effect remains unclear. The present study aimed to investigate the effect of NBP on rotenone-induced oxidative stress in microglia and its underlying mechanisms. The results demonstrated that NBP treatment significantly increased mitochondrial membrane potential and decreased ROS level in rotenone-induced microglia. Western blot analysis showed that NBP treatment promoted entry of nuclear respiratory factor-2 (Nrf2) into the nucleus, increased heme oxygenase-1 (HO-1) expression and decreased the level of the Nrf2 inhibitory protein, Kelch-like ECH-associated protein 1. Overall, the findings indicated that NBP inhibited rotenone-induced microglial oxidative stress via the Keap1/Nrf2/HO-1 pathway, suggesting that NBP may serve as a novel agent for the treatment of PD.

Rifampicin ameliorates lipopolysaccharide-induced cognitive and motor impairments via inhibition of the TLR4/MyD88/NF-κB signaling pathway in mice.

OBJECTIVES: Aberrant microglial responses promote neuroinflammation in neurodegenerative diseases. However, rifampicin's effect on cognitive and motor sequelae of inflammation remains unknown. Therefore, we investigated whether rifampicin exerts neuroprotection against lipopolysaccharide (LPS)-induced cognitive and motor impairments. METHODS: A mouse model of LPS-induced cognitive and motor impairment was established. Adult C57BL/6 mice were injected intraperitoneally with 25 mg/kg rifampicin 30 min before intraperitoneal microinjection of LPS (750 µg/kg) daily until study end. Treatments and behavioral experiments were performed once daily for 7 days. Behavioral tests and pathological/biochemical assays were performed to evaluate LPS-induced damage to the hippocampus and substantia nigra (SN). RESULTS: Rifampicin attenuated LPS-induced cognitive and motor impairments, based on performance in the behavioral tests. Rifampicin suppressed the release of pro-inflammatory mediators, including tumor necrosis factor-α, interleukin-1ß, and prostaglandin E2 in the serum and nitric oxide (NO) in brain tissue, and cyclooxygenase-2 and inducible nitric oxide synthase levels. Immunofluorescence revealed that rifampicin inhibited LPS-induced microglial activation in the hippocampus and SN, thus protecting the neurons. Rifampicin inhibited the activation of the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway. Rifampicin downregulated TLR4 and MyD88 protein levels and inhibited NF-κB inhibitor alpha and NF-κB inhibitor kinase beta phosphorylation, thus reducing p65 nuclear transfer by inhibiting NF-κB signaling activation in LPS-treated mice. CONCLUSION: Rifampicin protects against LPS-induced neuroinflammation and attenuates cognitive and motor impairments by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Our findings might aid the development of novel therapies to treat progressive neurodegenerative diseases.

Dynamical transition orbitals: A particle-hole description in real-time TDDFT dynamics.

We expand the concept of natural transition orbitals in the context of real-time time-dependent density functional theory (RT-TDDFT) and show its application in practical calculations. Kohn-Sham single-particle wavefunctions are propagated in RT-TDDFT simulation, and physical properties remain invariant under their unitary transformation. In this work, we exploit this gauge freedom and expand the concept of natural transition orbitals, which is widely used in linear-response TDDFT, for obtaining a particle-hole description in RT-TDDFT simulation. While linear-response TDDFT is widely used to study electronic excitation, RT-TDDFT can be employed more generally to simulate non-equilibrium electron dynamics. Studying electron dynamics in terms of dynamic transitions of particle-hole pairs is, however, not straightforward in the RT-TDDFT simulation. By constructing natural transition orbitals through projecting time-dependent Kohn-Sham wave functions onto occupied/unoccupied eigenstate subspaces, we show that linear combinations of a pair of the resulting hole/particle orbitals form a new gauge, which we refer to as dynamical transition orbitals. We demonstrate the utility of this framework to analyze RT-TDDFT simulations of optical excitation and electronic stopping dynamics in the particle-hole description.

Rifampicin Suppresses Amyloid-ß Accumulation Through Enhancing Autophagy in the Hippocampus of a Lipopolysaccharide-Induced Mouse Model of Cognitive Decline.

BACKGROUND: Alzheimer's disease (AD) is characterized by amyloid-ß (Aß) deposition. The metabolism of Aß is critically affected by autophagy. Although rifampicin is known to mediate neuroinflammation, the underlying mechanism by which rifampicin regulates the cognitive sequelae remains unknown. OBJECTIVE: Based on our previous findings that rifampicin possesses neuroprotective effects on improving cognitive function after neuroinflammation, we aimed to examine in this study whether rifampicin can inhibit Aß accumulation by enhancing autophagy in a mouse model of lipopolysaccharide (LPS)-induced cognitive impairment. METHODS: Adult C57BL/6 mice were intraperitoneally injected with rifampicin, chloroquine, and/or LPS every day for 7 days. Pathological and biochemical assays and behavioral tests were performed to determine the therapeutic effect and mechanism of rifampicin on the hippocampus of LPS-induced mice. RESULTS: We found that rifampicin ameliorated cognitive impairments in the LPS-induced mice. In addition, rifampicin attenuated the inhibition of autophagosome formation, suppressed the accumulation of Aß1-42, and protected the hippocampal neurons against LPS-induced damage. Our results further demonstrated that rifampicin improved the neurological function by promoting autophagy through the inhibition of Akt/mTOR/p70S6K signaling pathway in the hippocampus of LPS-induced mice. CONCLUSION: Rifampicin ameliorates cognitive impairment by suppression of Aß1-42 accumulation through inhibition of Akt/mTOR/p70S6K signaling and enhancement of autophagy in the hippocampus of LPS-induced mice.

USP8 protects against lipopolysaccharide-induced cognitive and motor deficits by modulating microglia phenotypes through TLR4/MyD88/NF-κB signaling pathway in mice.

Ubiquitin-specific protease 8 (USP8) regulates inflammation in vitro; however, the mechanisms by which USP8 inhibits neuroinflammation and its pathophysiological functions are not completely understood. In this study, we aimed to determine whether USP8 exerts neuroprotective effects in a mouse model of lipopolysaccharide (LPS)-induced cognitive and motor impairment. We commenced intracerebroventricular USP8 administration 7 days prior to i.p. injection of LPS (750 µg/kg). All treatments and behavioral experiments were performed once per day for 7 consecutive days. Behavioral tests and pathological/biochemical assays were performed to evaluate LPS-induced hippocampal damage. USP8 attenuated LPS-induced cognitive and motor impairments in mice. Moreover, USP8 downregulated several pro-inflammatory cytokines [nitric oxide (NO), tumor necrosis factor α (TNF-α), prostaglandin E2 (PGE2), and interleukin-1ß (IL-1ß)] in the serum and brain, and the relevant protein factors [inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2)] in the brain. Furthermore, USP8 upregulated the anti-inflammatory mediators interleukin (IL)-4 and IL-10 in the serum and brain, and promoted a shift from pro-inflammatory to anti-inflammatory microglial phenotypes. The LPS-induced microglial pro-inflammatory phenotype was abolished by TLR4 inhibitor and in TLR4-/- mice; these effects were similar to those of USP8 treatment. Mechanistically, we found that USP8 increased the expression of neuregulin receptor degradation protein-1 (Nrdp1), potently downregulated the expression of TLR4 and myeloid differentiation primary response protein 88 (MyD88) protein, and inhibited the phosphorylation of IκB kinase (IKK) ß and kappa B-alpha (IκBα), thereby reducing nuclear translocation of p65 by inhibiting the activation of the nuclear factor-kappaB (NF-κB) signaling pathway in LPS-induced mice. Our results demonstrated that USP8 exerts protective effects against LPS-induced cognitive and motor deficits in mice by modulating microglial phenotypes via TLR4/MyD88/NF-κB signaling.