Biology subjects

Peng, Y.

Publications and source records attributed to Peng, Y..

At least 145 records · Page 8Linked to original sources

bioRxiv2023

A comprehensive catalog with 100 million genes and 3,000 metagenome-assembled genomes from global cold seep sediments

Cold seeps harbor abundant and diverse microbes that represent a tremendous potential for biological applications and also have a significant influence on biogeochemical cycles. Though recent metagenomic studies have expanded our understanding of the microbial community and function of seep microorganisms, the knowledge of diversity and genetic repertoire of global seep microbes is lacking. Here, we collected a compilation of 165 metagenomic data from 16 cold seep sites across the globe to construct comprehensive gene and genome catalogs. The non-redundant gene catalog was comprised of 147 million genes (clustered at 95% amino acid identity), and 35.72% of them could not be assigned to a function with the currently available databases. A total of 3,164 species-level representative metagenome-assembled genomes (MAGs) are obtained, most of which (94.31%) belong to novel species. Of them, 81 ANME species are identified covering all subclades except ANME-2d, and 23 syntrophic SRB species spanning Seep-SRB1a Seep-SRB1g, and Seep-SRB2 clades. The non-redundant gene and MAGs catalogs are a valuable resource that enables expanded knowledge of the structure and functions of cold seep microbiomes.

microbiology↗

bioRxiv2023

Dysregulated Wnt and NFAT signaling in a Parkinson's disease LRRK2 G2019S knock-in model

BackgroundParkinsons disease (PD) is a progressive late-onset neurodegenerative disease leading to physical and cognitive decline. Mutations of leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. LRRK2 is a complex scaffolding protein with known regulatory roles in multiple molecular pathways. Two prominent examples of LRRK2-modulated pathways are Wingless/Int (Wnt) and nuclear factor of activated T-cells (NFAT) signaling. Both are well described key regulators of immune and nervous system development as well as maturation. The aim of this study was to establish the physiological and pathogenic role of LRRK2 in Wnt and NFAT signaling in the brain, as well as the potential contribution of the non-canonical Wnt/Calcium pathway. MethodsIn vivo cerebral Wnt and NFATc1 signaling activity was quantified in LRRK2 G2019S mutant knock-in (KI) and LRRK2 knockout (KO) male and female mice with repeated measures over 28 weeks, employing lentiviral luciferase biosensors, and analyzed using a mixed-effect model. To establish spatial resolution, we investigated tissues, and primary neuronal cell cultures from different brain regions combining luciferase signaling activity, immunohistochemistry, qPCR and western blot assays. Results were analyzed by unpaired t-test with Welchs correction or 2-way ANOVA with post hoc corrections. ResultsIn vivo Wnt signaling activity in LRRK2 KO and LRRK2 G2019S KI mice was increased significantly [~]3-fold, with a more pronounced effect in males ([~]4-fold) than females ([~]2-fold). NFATc1 signaling was reduced [~]0.5-fold in LRRK2 G2019S KI mice. Brain tissue analysis showed region-specific expression changes in Wnt and NFAT signaling components. These effects were predominantly observed at the protein level in the striatum and cerebral cortex of LRRK2 KI mice. Primary neuronal cell culture analysis showed significant genotype-dependent alterations in Wnt and NFATc1 signaling under basal and stimulated conditions. Wnt and NFATc1 signaling was primarily dysregulated in cortical and hippocampal neurons respectively. ConclusionsOur study further built on knowledge of LRRK2 as a Wnt and NFAT signaling protein. We identified complex changes in neuronal models of LRRK2 PD, suggesting a role for mutant LRRK2 in the dysregulation of NFAT, and canonical and non-canonical Wnt signaling.

neuroscience↗

bioRxiv2023

NRF2 deficiency promotes ferroptosis of astrocytes mediated by oxidative stress in Alzheimer's disease

Oxidative stress is involved in the pathogenesis of Alzheimers disease (AD), which is linked to reactive oxygen species (ROS), lipid peroxidation, and neurotoxicity. Emerging evidence suggests a role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a major source of antioxidant response elements in AD. The molecular mechanism of oxidative stress and ferroptosis in astrocytes in AD is not yet fully understood. Here, we aim to investigate the mechanism by which Nrf2 regulates the ferroptosis of astrocytes in AD. Postmortem frontal cortex tissues from patients with AD and nondemented controls and brain tissue from the 3xTg AD mouse model and wild-type mice (10 months old) were used. Immunofluorescence staining for Nrf2, the ROS marker NADPH oxidase 4 (NOX4), and GFAP was performed. We further induced Nrf2 deficiency in mouse astrocytes by using RNAi and assessed the changes in ROS, ferroptosis, lipid peroxidation, and mitochondrial dysfunction by using western blotting and immunofluorescence staining. We found decreased expression of Nrf2 and upregulated expression of NOX4 in the frontal cortex from patients with AD and in the cortex of 3xTg mice compared to control mice. We demonstrated that Nrf2 deficiency led to ferroptosis-dependent oxidative stress-induced ROS with downregulated heme oxygenase-1 and glutathione peroxidase 4 and upregulated cystine glutamate expression. Moreover, Nrf2 deficiency increased lipid peroxidation, DNA oxidation, and mitochondrial fragmentation in mouse astrocytes. In conclusion, these results suggest that Nrf2 promotes ferroptosis of astrocytes involving oxidative stress in AD.

neuroscience↗

bioRxiv2023

Viruses in deep-sea cold seep sediments harbor diverse survival mechanisms and remain genetically conserved within species

Deep sea cold seep sediments have been discovered to harbor novel, abundant, and diverse bacterial and archaeal viruses. However, little is known about viral genetic features and evolutionary patterns in these environments. Here, we examined the evolutionary ecology of viruses across active and extinct seep stages in the area of Haima cold seeps in the South China Sea. Diverse antiviral defense systems in 487 microbial genomes spanning 43 families inform the dynamics of host-virus interactions. Accordingly, a total of 338 viral operational taxonomic units are identified and linked to 36 bacterial and archaeal phyla. Cold seep viruses are predicted to harbor diverse adaptive strategies to persist in this environment, including counter-defense systems, reverse transcriptases, auxiliary metabolic genes, and alternative genetic code assignments. Extremely low nucleotide diversity is observed in cold seep viral populations, being influenced by factors including microbial host, sediment depth and cold seep stage. Most cold seep viral genes are under strong purifying selection with trajectories that differ depending on whether cold seeps are active or extinct. This work sheds light on the understanding of environmental adaptation mechanisms and evolutionary patterns of viruses in the sub-seafloor biosphere.

microbiology↗

bioRxiv2023

DNA 5-methylcytosine regulates genome-wide formation of G-quadruplex structures

G-quadruplex structures (G4s) have been identified in genomes of multiple organisms and proven to play important epigenetic regulatory roles in various cellular functions. However, the G4 formation mechanism remains largely unknown. Here, we found a negative correlation between DNA 5mC methylation and G4 abundance. The abundance of genomic G4s significantly increased when the whole-genome methylation level was reduced in DNMT1-knockout cells. This increase was then suppressed by DNMT1 over-expression. And more G4s were detected in the hypomethylated cancer cell line HepG2 and rectal cancer tissues. Besides, 5mC modification significantly inhibited G4 formation of the potential G-quadruplex sequences (PQSs). The transcription of genes with 5mC modification sites in their promoter PQSs was affected after treatment with G4 stabilizer pyridostatin or methylation inhibitor 5-aza-dC. The global reduction of genomic methylation elevates gene transcription levels through increased G4s. Taken together, DNA 5mC methylation prevents PQSs from folding into G4s in genomes.

molecular biology↗

bioRxiv2023

Gastrodin ameliorates synaptic impairment, reestablishes mitochondrial membrane potential and reduces oxidative stress in N2a/APP cells through the ERK1/2 and GSK-3beta pathways

Alzheimers disease (AD) is featured by abnormal {beta}-amyloid (A{beta}) deposition, neurofibrillary tangle formation, downstream mitochondrial dysfunction, oxidative stress, and synaptic loss. Gastrodin, a phenolic glycoside, has shown neuroprotective effect and used in the treatment of a range of brain diseases. Here we aim to assess the mechanisms and signaling pathways involved in the neuroprotective effect of gastrodin in murine neuroblastoma N2a cells expressing human Swedish mutant amyloid precursor protein (N2a/APP). The levels of pre- and postsynaptic proteins, amyloid precursor protein C-terminal fragments (APP-CTFs), levels of tau, glycogen synthase kinase-3 {beta} (GSK-3{beta}), extracellular regulated kinase (ERK), and c-Jun N-terminal Kinase (JNK) were assessed by Western blotting. Flow cytometry assays for mitochondrial membrane potential (JC1) and reactive oxidative stress, as well as immunofluorescence staining for lipid peroxidation (4{square}hydroxynonenal) and DNA oxidation (8{square}hydroxy{square}2{square}deoxyguanosine), were performed. We found that gastrodin treatment increased the levels of presynaptic SNAP25, synaptophysin, and postsynaptic PSD95, reduced phosphorylated tau protein Ser396, and APP-CTFs in N2a/APP cells. In addition, gastrodin reduced the levels of reactive oxygen species generation, lipid peroxidation, and DNA oxidation, reestablished mitochondrial membrane potential. Upregulated levels of phosphorylated-GSK-3{beta}, reduced levels of phosphorylated-ERK, and phosphorylated-JNK were involved the protective effect of gastrodin. In conclusion, we demonstrated a neuroprotective effect of gastrodin in N2a/APP cell line.

neuroscience↗

bioRxiv2023

Redistribution and activation of CD16brightCD56dim NK cell subset to fight against Omicron subvariant BA.2 after COVID-19 vaccination

With the alarming surge in COVID-19 cases globally, vaccination must be prioritised to achieve herd immunity. Immune dysfunction is detected in the majority of patients with COVID-19; however, it remains unclear whether the immune responses elicited by COVID-19 vaccination function against the Omicron subvariant BA.2. Of the 508 Omicron BA.2-infected patients enrolled, 102 were unvaccinated controls and 406 were vaccinated. Despite the presence of clinical symptoms in both groups, vaccination led to a significant decline in nausea or vomiting, abdominal pain, headache, pulmonary infection, overall clinical symptoms, and a moderate rise in body temperature. Omicron BA.2-infected individuals were also characterised by a mild increase in both serum pro- and anti-inflammatory cytokine levels after vaccination. There were no significant differences or trend changes between T and B lymphocyte subsets; however, a significant expansion of NK lymphocytes in COVID-19-vaccinated patients was observed. Moreover, the most effective CD16brightCD56dim subsets of NK cells showed increased functional capacities, as evidenced by a significantly greater IFN-{gamma} secretion and stronger cytotoxic potential in Omicron BA.2-infected patients after vaccination. Collectively, these results suggest that COVID-19 vaccination interventions promote the redistribution and activation of CD16brightCD56dim NK cell subsets against viral infections, and could facilitate the clinical management of Omicron BA.2-infected patients.

immunology↗

bioRxiv2023

Myricetin protected against Aβ oligomer-induced synaptic impairment, mitochondrial function and oxidative stress in SH-SY5Y cells via ERK1/2/GSK-3β pathways

Alzheimers disease is characterized by abnormal {beta}-amyloid (A{beta}) plaque accumulation, tau hyperphosphorylation, reactive oxidative stress, mitochondrial dysfunction and synaptic loss. Myricetin, a dietary flavonoid, has been shown to have neuroprotective effects in vitro and in vivo. Here, we aimed to elucidate the mechanism and pathways involved in myricetins protective effect on the toxicity induced by the A{beta}42 oligomer. Neuronal SH-SY5Y cells were pretreated with myricetin before incubation with A{beta}42 oligomer. The levels of pre- and postsynaptic proteins, mitochondrial division and fusion proteins, glycogen synthase kinase-3 {beta} (GSK-3{beta}) and extracellular regulated kinase (ERK) 1/2 were assessed by Western blotting. Flow cytometry assays for mitochondrial membrane potential (JC1) and reactive oxidative stress, as well immunofluorescence staining for lipid peroxidation (4-HNE) and DNA oxidation (8-OHdG), were performed. We found that myricetin prevented A{beta}42 oligomer-induced tau phosphorylation and the reduction in pre/postsynaptic proteins. In addition, myricetin reduced reactive oxygen species generation, lipid peroxidation, and DNA oxidation induced by the A{beta}42 oligomer. Moreover, myricetin prevented the A{beta}42 oligomer-induced reduction in mitochondrial fusion proteins (mitofusin-1, mitofusin-2), fission protein (dynamin-related protein 1) phosphorylation, and mitochondrial membrane potential via the associated GSK-3{beta} and ERK 1/2 signaling pathways. In conclusion, this study provides new insight into the neuroprotective mechanism of myricetin against A{beta}42 oligomer-induced toxicity.

neuroscience↗

bioRxiv2023

Benchmark and optimization of AlphaFold structures based virtual screening strategy

Recent advancements in artificial intelligence such as AlphaFold, have enabled more accurate prediction of protein three-dimensional structure from amino acid sequences. This has attracted significant attention, especially for the application of AlphaFold in drug discovery. However, how to take full advantage of AlphaFold to assist with virtual screening remains elusive. We evaluate the AlphaFold structures of 51 selected targets from the DUD-E database in virtual screening. Our analyses show that the virtual screening performance of about 35% of the AlphaFold structures is equivalent to that of DUD-E structures, and about 25% of the AlphaFold structures yield better results than the DUD-E structures. Remarkably, AlphaFold structures produce slightly better results than the Apo structures. Moreover, we develop a new consensus scoring method based on Z-score standardization and exponential function, which shows improved screening performance compared to traditional scoring methods. By implementing a multi-stage virtual screening process and the new consensus scoring method, we are able to improve the speed of virtual screening by about nine times without compromising the enrichment factor. Overall, our results provide insights into the potential use of AlphaFold in drug discovery and highlight the value of consensus scoring and multi-stage virtual screening.

bioinformatics↗

bioRxiv2022

Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection.

We analyzed the dynamics of the earliest T cell response to SARS-COV-2. A wave of TCRs strongly but transiently expand during infection, frequently peaking the same week as the first positive PCR test. These expanding TCR CDR3s were enriched for sequences functionally annotated as SARS-COV-2 specific. Most epitopes recognized by the expanding TCRs were highly conserved between SARS-COV-2 strains, but not with circulating human coronaviruses. Many expanding CDR3s were also present at high precursor frequency in pre-pandemic TCR repertoires. A similar set of early response TCRs specific for lymphocytic choriomeningitis virus epitopes were also found at high frequency in the pre-infection naive repertoire. High frequency naive precursors may allow the T cell response to respond rapidly during the crucial early phases of acute viral infection. One-Sentence SummaryHigh frequency naive precursors underly the rapid T cell response during the crucial early phases of acute viral infection.

immunology↗

bioRxiv2022

Exploring the genome and protein space of viruses

Recent metagenomic studies have identified a vast number of viruses. However, the systematic assessment of the true genetic diversity of the whole virus community on our planet remains to be investigated. Here, we explored the genome and protein space of viruses by simulating the process of virus discovery in viral metagenomic studies. Among multiple functions, the power function was found to best fit the increasing trends of virus diversity and was therefore used to predict the genetic space of viruses. The estimate suggests that there are at least 8.23e+08 viral Operational Taxonomic Units (vOTUs) and 1.62e+09 viral protein clusters on Earth when assuming the saturation of the virus genetic space, taking into account the balance of costs and the identification of novel viruses. Its noteworthy that less than 3% of the viral genetic diversity has been uncovered thus far, emphasizing the vastness of the unexplored viral landscape. To saturate the genetic space, a total of 3.08e+08 samples would be required. Analysis of viral genetic diversity by ecosystem yielded estimates consistent with those mentioned above. Furthermore, the estimate of the virus genetic space remained robust when accounting for the redundancy of sampling, sampling time, sequencing platform, and parameters used for protein clustering. This study provides a guide for future sequencing efforts in virus discovery and contributes to a better understanding of viral diversity in nature.

microbiology↗

bioRxiv2022

Global terrestrial nitrogen uptake and nitrogen use efficiency

Plant biomass production (BP), nitrogen uptake (Nup) and their ratio, nitrogen use efficiency (NUE), must be quantified to understand how nitrogen (N) cycling constrains terrestrial carbon (C) uptake. But the controls of key plant processes determining Nup and NUE, including BP, C and N allocation, tissue C:N ratios and N resorption efficiency (NRE), remain poorly known. We compiled measurements from 804 forest and grassland sites and derived regression models for each of these processes with growth temperature, vapour pressure deficit, stand age, soil C:N ratio, fAPAR (remotely sensed fraction of photosynthetically active radiation absorbed by green vegetation) and growing-season average daily incident photosynthetic photon flux density (gPPFD) (effectively the seasonal concentration of light availability, which increases polewards) as predictors. An empirical model for leaf N was based on optimal photosynthetic capacity (a function of gPPFD and climate) and observed leaf mass-per-area. The models were used to produce global maps of Nup and NUE. Global BP was estimated as 72 Pg C/yr; Nup as 950 Tg N/yr; and NUE as 76 gC/gN. Forest BP was found to increase with growth temperature and fAPAR and to decrease with stand age, soil C:N ratio and gPPFD. Forest NUE is controlled primarily by climate through its effect on C allocation - especially to leaves, being richer in N than other tissues. NUE is greater in colder climates, where N is less readily available, because belowground allocation is increased. NUE is also greater in drier climates because leaf allocation is reduced. NRE is enhanced (further promoting NUE) in both cold and dry climates. These findings can provide observationally based benchmarks for model representations of C-N cycle coupling. State-of-the-art vegetation models in the TRENDY ensemble showed variable performance against these benchmarks, and models including coupled C-N cycling produced relatively poor simulations of Nup and NUE.

ecology↗

bioRxiv2022

Multi-omics Analysis Identifies IgG2b Class-Switching with ALCAM-CD6 Co-Stimulation in Lymph Nodes During Advanced Inflammatory-Erosive Arthritis

Defective lymphatic drainage and B-cell translocation into joint-draining lymph node sinuses are pathogenic phenomena in patients with severe rheumatoid arthritis (RA). However, the molecular mechanisms underlying this lymphatic dysfunction remain poorly understood. Here, by utilizing spatial and single-cell transcriptomics in tumor necrosis factor transgenic (TNF-Tg) mice, we characterized functional genomic changes in popliteal lymph nodes (PLNs) of "Early" and "Advanced" RA to determine the mechanisms orchestrating B-cell differentiation. We first show that Ighg2b expression localized to Marco+ sinuses and negatively correlated with bone volumes in ipsilateral joints. We further reveal that Advanced PLNs exhibited a concomitant accumulation of iron-laden macrophages and T-cells. Mechanistically, crosstalk between ALCAM+ macrophages and CD6+ T-cells was identified as a co-stimulatory pathway promoting IgG2b class-switching. These findings were validated by immunohistochemistry, flow cytometry, ELISPOT, and clinical correlates. Collectively, we propose that ALCAM-CD6 co-stimulation activates T cells, initiating IgG2b class-switching and plasma cell differentiation in RA flare.

immunology↗

bioRxiv2022

Transposable elements orchestrate subgenome-convergent and -divergent transcription in common wheat

The success of common wheat as the global staple crop is derived from genome diversity and redundancy as a result of allopolyploidization [1-3], giving rise to the major question how the divergent and convergent transcription among different subgenomes are achieved and harmonized in a single cell. The regulatory information is largely encoded in DNA regulatory elements (REs) interpreted by sequence specific transcription factors (TFs). Here, we created a catalog of genome-wide TF-binding sites (TFBS) to assemble an extensive wheat regulatory network comprising connections among 189 TFs and 3,714,431 REs, which enhances the understanding of wheat regulatory mechanisms on an unprecedented scale. A significant fraction of subgenome-divergent TFBS are derived from recent subgenome-asymmetric expansion of particular transposable element (TE) families. In contrary, TFBS derived from ancient TE expansion largely underwent parallel purifying selection during independent evolution of each subgenome, despite extensive unbalanced turnover of flanking TEs. Altogether, the subgenome-convergent and -divergent regulation in common wheat is orchestrated via differential evolutionary selection on paleo- and neo-TEs.

bioinformatics↗

bioRxiv2022

Chemical inhibition of PIN auxin transporters by the anti-inflammatory drug Naproxen

The phytohormone auxin plays central roles in many growth and developmental processes in plants. Development of chemical tools targeting the auxin pathway is useful for both plant biology and agriculture. Here we uncover that Naproxen, a synthetic compound with anti-inflammatory activity in humans, acts as an auxin transport inhibitor targeting PIN transporters in plants. Physiological experiments indicate that exogenous Naproxen treatment affects pleiotropic auxin-regulated developmental processes. Further cellular and biochemical evidence supports that Naproxen suppresses auxin transport, specifically PIN-mediated auxin efflux. Moreover, biochemical and structural analysis confirms that Naproxen binds directly to PIN1 protein, via the same binding cavity as the IAA substrate. Thus, by combining cellular, biochemical, and structural approaches, this study well establishes that Naproxen is a PIN inhibitor and elucidates the underlying mechanisms. Further use of the compound may advance our understanding on the molecular mechanisms of PIN-mediated auxin transport, and expand our toolkit in auxin biology and agriculture.

plant biology↗

bioRxiv2022

Heterosynaptic Plasticity of the Visuo-auditory Projection Requires Cholecystokinin released from Entorhinal Cortex Afferents

The entorhinal cortex is involved in establishing enduring visuo-auditory associative memory in the neocortex. Here we explored the mechanisms underlying this synaptic plasticity related to projections from the visual and entorhinal cortices to the auditory cortex, using optogenetics of dual pathways. High-frequency laser stimulation (HFLS) of the visuo-auditory projection did not induce long-term potentiation (LTP). However, after pairing with sound stimulus, the visuo-auditory inputs were potentiated following either infusion of cholecystokinin (CCK) or HFLS of the entorhino-auditory CCK-expressing projection. Combining retrograde tracing and RNAscope in situ hybridization, we show that CCK expression is higher in entorhinal cortex neurons projecting to the auditory cortex than in those originating from the visual cortex. In the presence of CCK, potentiation in the neocortex occurred when the pre-synaptic input arrived 200 ms before post-synaptic firing, even after just five trials of pairing. Behaviorally, inhibition of CCK signaling blocked the generation of associative memory. Our results indicate that neocortical visuo-auditory association is formed through heterosynaptic plasticity, which depends on release of CCK in the neocortex mostly from entorhinal afferents.

neuroscience↗

bioRxiv2022

Abnormal intrinsic neural timescale in Parkinson's disease

BACKGROUND: Numerous studies indicate altered peak latency of event-related potential and altered time variability of brain function network in Parkinsons disease (PD), and the intrinsic neural timescale estimated how long neural information stored in a local brain area has been specialized. However, it was unclear whether PD patients exhibited abnormal intrinsic timescales and accompanied with abnormal grey matter and whether PD patients exhibited different temporal feature at different stages. STUDY TYPE: Prospective. POPULATION: 74 PD patients, including 44 patients in the early stage (PD-ES) and 30 patients in the late stage (PD-LS), and 73 healthy controls (HC). SEQUENCE: 3.0T MRI scanner; prototypic T1 magnetization prepared rapid acquisition gradient echo (MPRAGE); resting-state fMRI. ASSESSMENT: the intrinsic timescales were estimated by using the magnitude of the autocorrelation of intrinsic neural signals. Voxel-based morphometry (VBM) was performed to calculate the grey matter volume (GMV) in the whole brain. STATISTICAL TEST: Analysis of variance (ANOVA); two-sample t-tests; Spearman rank correlation analysis; Mann-Whitney U test; Kruskal-Wallis H test. RESULTS: We identified that the PD group had abnormal intrinsic timescales in bilateral lingual and calcarine gyri, bilateral postcentral and precentral gyri, and the right middle cingulum gyrus, which correlated with the symptom severity and the GMV. Moreover, longer timescale in the right middle frontal gyrus were also found in the PD group. Increasingly, the PD-ES group had longer timescales in the anterior cortical regions, whereas the PD-LS group had shorter timescales in the posterior cortical regions. DATA CONCLUSION: Our findings suggest that PD patients exhibit abnormal intrinsic timescales in visual, sensorimotor, and cognitive systems and distinct patterns of intrinsic timescales and GMV in cerebral cortex at different stages, which might provide new insights for the neural substrate of PD.

neuroscience↗

bioRxiv2022

Quercetin reduces APP expression, oxidative stress and mitochondrial dysfunction in the N2a/APPswe cells via ERK1/2 and AKT pathways

Abnormal amyloid-{beta} (A{beta}) abnormal accumulation and oxidative stress play important roles in Alzheimers disease (AD). Quercetin has been reported to possess antioxidant and anti-inflammatory properties, and thus of therapeutic interests for neurodegenerative disorders. In the present study, we aimed to characterize the mechanisms by which quercetin exerts neuroprotective effects in murine neuroblastoma N2a cells stably expressing human Swedishh mutant amyloid precursor protein (APP). Quercetin treatment exhibited low cytoxicity, attenuated APP expression and APP-induced oxidative neurotoxicity in N2a/APP cells. We found that quercetin effected via the down-regulation of phospho-extracellular signal{square}regulated protein kinase (p-ERK1/2) pathway and up-regulation of phospho-protein kinase B (p-AKT) pathway in N2a/APP cells. In addition, quercetin ameliorated the elevated levels of reactive oxygen species using DCFH-DA flow-cytometry in N2a/APP cells, lipid peroxidation using (4-HNE), and DNA oxidation (8-OHdG assays). Quercetin ameliorated the loss of mitochondrial membrane potential using JC-1 fluorescence assay in N2a/APP cells in a dose-dependent mannor. In conclusion, we domenstrated the neuroprotective effects of quercetin against the APP expression induced oxidative neurotoxicity, impairment of mitochondrial function and oxidative stress through inactivation of the ERK1/2 signaling pathway and activation of AKT signaling pathways.

neuroscience↗