Targeting vulnerable microcircuits in the ventral hippocampus of male transgenic mice to rescue Alzheimer-like social memory loss.

BACKGROUND: Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease (AD), which is closely related to tau pathology and hippocampal impairment. Due to the heterogeneity of brain neurons, the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear. Therefore, further investigation is necessary. METHODS: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis, social behavioural tests, hippocampal electrophysiology, immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine the effects of these agents on social memory in mice. RESULTS: The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, vCA1, especially its excitatory and parvalbumin (PV) neurons, were fully filled with mislocated and phosphorylated tau (p-Tau). This finding was not observed for dorsal hippocampal CA1 (dCA1). The overexpression of human tau (hTau) in excitatory and PV neurons mimicked AD-like tau accumulation, significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory. Notably, 1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB (TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory. CONCLUSION: This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.

Roller Microneedle Combined with Tranexamic Acid Solution in Treating Melasma.

Melasma, a common, acquired facial pigmentation skin disorder, presents a straightforward clinical diagnosis but poses challenges in terms of effective management. The precise underlying causes of melasma remain elusive, and the current therapeutic approaches predominantly encompass pharmaceutical and laser interventions, with limited efficacy. Transdermal administration stands as a prevalent treatment method for melasma, often facilitated by the application of microneedles. Among these, tranexamic acid emerges as a frequently employed therapeutic agent. A subset of microneedles, known as roller microneedles, plays a significant role in this approach by delicately puncturing the epidermis with multiple fine needles, synergizing with drug delivery. This methodology not only enhances drug absorption but also augments treatment efficacy while minimizing tissue trauma. These attributes forecast promising avenues for the treatment of melasma. This article primarily introduces the combination of roller microneedle and tranexamic acid solution in the treatment of melasma and demonstrates the efficacy of roller microneedle and tranexamic acid solution in the treatment of melasma through clinical cases.

Variation of Ferroptosis-Related Markers in HaCaT Cell Photoaging Models Induced by UVB.

Objective: To investigate the variation of ferroptosis-related markers in HaCaT cell photoaging models induced by ultraviolet-B (UVB). Methods: UVB-treated HaCaT cells served as the model (UVB group) for cellular photoaging, whereas untreated HaCaT cells served as the control group. HaCaT cells were exposed to UVB and the ferroptosis inhibitor Ferrostatin-1 (Fer-1) as part of the UVB+Fer-1 group, and co-cultured with the ferroptosis inducer Erastin as part of the UVB+Erastin group. Reactive oxygen species (ROS) detection kit and senescence-related ß galactosidase (SA-ß-gal) staining were used to evaluate the senescence of HaCaT cells. Lipid reactive oxygen species were detected by C11 BODIPY581/591 probe and mitochondrial morphology was observed by transmission electron microscopy. The mRNA expressions of glutathione peroxidase 4 (GPX4) and ferroptosis-suppressor-protein 1 (FSP1) were detected by real-time reverse transcription-PCR (RT-RCP), and the level of GPX4 protein was measured by immunofluorescence assay. Results: The UVB group had considerably greater levels of ROS, SA-ß-gal, and lipid reactive oxygen species than the control group. The UVB group's mitochondrial volume was reduced, the membrane density increased, and the mitochondrial crest decreased or even disappeared. GPX4 and FSP1 expression levels were similarly found to be lower in the UVB group. Furthermore, the positive rate of SA-ß-gal and lipid reactive oxygen species in the UVB+Fer-1 group was much lower than in the UVB group, but it was reverse in the UVB+Erastin group. This study showed that induced ferroptosis can aggravate aging, and vice versa. Conclusion: According to the findings, ferroptosis may be linked to UVB-induced skin photoaging, which could be attenuated by inhibition of ferroptosis.

RIPK1 and RIPK3 inhibitors: potential weapons against inflammation to treat diabetic complications.

Diabetes mellitus is a metabolic disease that is characterized by chronic hyperglycemia due to a variety of etiological factors. Long-term metabolic stress induces harmful inflammation leading to chronic complications, mainly diabetic ophthalmopathy, diabetic cardiovascular complications and diabetic nephropathy. With diabetes complications being one of the leading causes of disability and death, the use of anti-inflammatories in combination therapy for diabetes is increasing. There has been increasing interest in targeting significant regulators of the inflammatory pathway, notably receptor-interacting serine/threonine-kinase-1 (RIPK1) and receptor-interacting serine/threonine-kinase-3 (RIPK3), as drug targets for managing inflammation in treating diabetes complications. In this review, we aim to provide an up-to-date summary of current research on the mechanism of action and drug development of RIPK1 and RIPK3, which are pivotal in chronic inflammation and immunity, in relation to diabetic complications which may be benefit for explicating the potential of selective RIPK1 and RIPK3 inhibitors as anti-inflammatory therapeutic agents for diabetic complications.

Serum CHI3L1 as a biomarker of interstitial lung disease in rheumatoid arthritis.

Background: Interstitial lung disease (ILD) is a relatively prevalent extra-articular manifestation of rheumatoid arthritis (RA) and contributes to significant morbidity and mortality. This study aimed to analyze the association between chitinase-3 like-protein-1(CHI3L1) and the presence of RA-ILD. Methods: A total of 239 RA patients fulfilling the American Rheumatism Association (ACR) 1987 revised criteria were enrolled and subclassified as RA-ILD and RA-nILD based on the results of high-resolution computed tomography scans (HRCT) of the chest. The disease activity of RA was assessed by Disease Activity Score for 28 joints (DAS28) and categorized as high, moderate, low, and remission. Chemiluminescence immunoassays were applied to determine the serum levels of CHI3L1. Univariate analysis was performed and the receiver operating characteristics (ROC) curves were plotted to evaluate the correlation between RA-ILD and CHI3L1. Results: Among the eligible RA patients studied, 60 (25.1%) patients were diagnosed with RA-ILD. Compared with RA-nILD, RA patients with ILD had significantly higher median age (median [IQR], 68.00 [62.00-71.75] vs 53.00 [40.00-63.00], p<0.001) and a higher proportion of males (21 (35.0%) vs 30 (16.8%), p=0.003). Notably, differences in DAS28 scores between the two groups were not observed. The serum level of CHI3L1 was significantly higher in RA-ILD patients (median [IQR], 69.69 [44.51-128.66] ng/ml vs 32.19 [21.63-56.99] ng/ml, p<0.001). Furthermore, the areas under the curve (AUC) of CHI3L1 attained 0.74 (95% confidence interval [CI], 0.68-0.81, p<0.001) in terms of identifying patients with RA-ILD from those without ILD. Similar trends were seen across the spectrum of disease activity based on DAS28-ESR. Conclusion: Our findings of elevated serum CHI3L1 levels in RA-ILD patients suggest its possible role as a biomarker to detect RA-ILD noninvasively.

Ferroptosis: new insight into the mechanisms of diabetic nephropathy and retinopathy.

Diabetic nephropathy (DN) and diabetic retinopathy (DR) are the most serious and common diabetes-associated complications. DN and DR are all highly prevalent and dangerous global diseases, but the underlying mechanism remains to be elucidated. Ferroptosis, a relatively recently described type of cell death, has been confirmed to be involved in the occurrence and development of various diabetic complications. The disturbance of cellular iron metabolism directly triggers ferroptosis, and abnormal iron metabolism is closely related to diabetes. However, the molecular mechanism underlying the role of ferroptosis in DN and DR is still unclear, and needs further study. In this review article, we summarize and evaluate the mechanism of ferroptosis and its role and progress in DN and DR, it provides new ideas for the diagnosis and treatment of DN and DR.

Poststress social isolation exerts anxiolytic effects by activating the ventral dentate gyrus.

After aversive stress, people either choose to return to their previously familiar social environment or tend to adopt temporary social withdrawal to buffer negative emotions. However, which behavior intervention is more appropriate and when remain elusive. Here, we unexpectedly found that stressed mice experiencing social isolation exhibited less anxiety than those experiencing social contact. Within the first 24 h after returning to their previous social environment, mice experienced acute restraint stress (ARS) displayed low social interest but simultaneously received excessive social disturbance from their cage mates, indicating a critical time window for social isolation to balance the conflict. To screen brain regions that were differentially activated between the poststress social isolation and poststress social contact groups, we performed ΔFosB immunostaining and found that ΔFosB + signals were remarkably increased in the vDG of poststress social isolation group compared with poststress social contact group. There were no significant differences between the two groups in the other anxiety- and social-related brain regions, such as prelimbic cortex, infralimbic cortex, nucleus accumbens, etc. These data indicate that vDG is closely related to the differential phenotypes between the poststress social isolation and poststress social contact groups. Electrophysiological recording, further, revealed a higher activity of vDG in the poststress social isolation group than the poststress social contact group. Chemogenetically inhibiting vDG excitatory neurons within the first 24 h after ARS completely abolished the anxiolytic effects of poststress social isolation, while stimulating vDG excitatory neurons remarkably reduced anxiety-like behaviors in the poststress social contact group. Together, these data suggest that the activity of vDG excitatory neurons is essential and sufficient to govern the anxiolytic effect of poststress social isolation. To the best of our knowledge, this is the first report to uncover a beneficial role of temporal social isolation in acute stress-induced anxiety. In addition to the critical 24-h time window, activation of vDG is crucial for ameliorating anxiety through poststress social isolation.

Ferroptosis, necroptosis and cuproptosis: Novel forms of regulated cell death in diabetic cardiomyopathy.

Diabetes is a common chronic metabolic disease, and its incidence continues to increase year after year. Diabetic patients mainly die from various complications, with the most common being diabetic cardiomyopathy. However, the detection rate of diabetic cardiomyopathy is low in clinical practice, and targeted treatment is lacking. Recently, a large number of studies have confirmed that myocardial cell death in diabetic cardiomyopathy involves pyroptosis, apoptosis, necrosis, ferroptosis, necroptosis, cuproptosis, cellular burial, and other processes. Most importantly, numerous animal studies have shown that the onset and progression of diabetic cardiomyopathy can be mitigated by inhibiting these regulatory cell death processes, such as by utilizing inhibitors, chelators, or genetic manipulation. Therefore, we review the role of ferroptosis, necroptosis, and cuproptosis, three novel forms of cell death in diabetic cardiomyopathy, searching for possible targets, and analyzing the corresponding therapeutic approaches to these targets.

Olfactory Threshold Test as a Quick Screening Tool for Cognitive Impairment: Analysis of Two Independent Cohorts.

BACKGROUND: Olfactory dysfunction appears prior to cognitive decline, and thus it has been suggested to be an early predictor of Alzheimer's disease. However, it is currently not known whether and how olfactory threshold test could serve as a quick screening tool for cognitive impairment. OBJECTIVE: To define olfactory threshold test for screening cognitive impairment in two independent cohorts. METHODS: The participants are comprised of two cohorts in China, 1,139 inpatients with type 2 diabetes mellitus (T2DM, Discovery cohort) and 1,236 community-dwelling elderly (Validation cohort). Olfactory and cognitive functions were evaluated by Connecticut Chemosensory Clinical Research Center test and Mini-Mental State Examination (MMSE), respectively. Regression analyses and receiver operating characteristic (ROC) analyses were carried out to determine the relation and discriminative performance of the olfactory threshold score (OTS) regarding identification of cognition impairment. RESULTS: Regression analysis showed that olfactory deficit (reducing OTS) was correlated with cognitive impairment (reducing MMSE score) in two cohorts. ROC analysis revealed that the OTS could distinguish cognitive impairment from cognitively normal individuals, with mean area under the curve values of 0.71 (0.67, 0.74) and 0.63 (0.60, 0.66), respectively, but it failed to discriminate dementia from mild cognitive impairment. The cut-off point of 3 showed the highest validity for the screening, with the diagnostic accuracy of 73.3% and 69.5%. CONCLUSION: Reducing OTS is associated with cognitive impairment in T2DM patients and the community-dwelling elderly. Therefore, olfactory threshold test may be used as a readily accessible screening tool for cognitive impairment.

Changes of serum IgG glycosylation patterns in rheumatoid arthritis.

BACKGROUND: RA is a common chronic and systemic autoimmune disease, and the diagnosis is based significantly on autoantibody detection. This study aims to investigate the glycosylation profile of serum IgG in RA patients using high-throughput lectin microarray technology. METHOD: Lectin microarray containing 56 lectins was applied to detect and analyze the expression profile of serum IgG glycosylation in 214 RA patients, 150 disease controls (DC), and 100 healthy controls (HC). Significant differential glycan profiles between the groups of RA and DC/HC as well as RA subgroups were explored and verified by lectin blot technique. The prediction models were created to evaluate the feasibility of those candidate biomarkers. RESULTS: As a comprehensive analysis of lectin microarray and lectin blot, results showed that compare with HC or DC groups, serum IgG from RA patients had a higher affinity to the SBA lectin (recognizing glycan GalNAc). For RA subgroups, RA-seropositive group had higher affinities to the lectins of MNA-M (recognizing glycan mannose) and AAL (recognizing glycan fucose), and RA-ILD group had higher affinities to the lectins of ConA (recognizing glycan mannose) and MNA-M while a lower affinity to the PHA-E (recognizing glycan Galß4GlcNAc) lectin. The predicted models indicated corresponding feasibility of those biomarkers. CONCLUSION: Lectin microarray is an effective and reliable technique for analyzing multiple lectin-glycan interactions. RA, RA-seropositive, and RA-ILD patients exhibit distinct glycan profiles, respectively. Altered levels of glycosylation may be related to the pathogenesis of the disease, which could provide a direction for new biomarkers identification.

Discovering new peripheral plasma biomarkers to identify cognitive decline in type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is an independent risk factor of Alzheimer's disease (AD), and thus identifying who among the increasing T2DM populations may develop into AD is important for early intervention. By using TMT-labeling coupled high-throughput mass spectrometry, we conducted a comprehensive plasma proteomic analysis in none-T2DM people (Ctrl, n = 30), and the age-/sex-matched T2DM patients with mild cognitive impairment (T2DM-MCI, n = 30) or T2DM without MCI (T2DM-nMCI, n = 25). The candidate biomarkers identified by proteomics and bioinformatics analyses were verified by ELISA, and their diagnostic capabilities were evaluated with machine learning. A total of 53 differentially expressed proteins (DEPs) were identified in T2DM-MCI compared with T2DM-nMCI patients. These DEPs were significantly enriched in multiple biological processes, such as amyloid neuropathies, CNS disorders, and metabolic acidosis. Among the DEPs, alpha-1-antitrypsin (SERPINA1), major viral protein (PRNP), and valosin-containing protein (VCP) showed strong correlation with AD high-risk genes APP, MAPT, APOE, PSEN1, and PSEN2. Also, the levels of PP2A cancer inhibitor (CIP2A), PRNP, corticotropin-releasing factor-binding protein (CRHBP) were significantly increased, while the level of VCP was decreased in T2DM-MCI patients compared with that of the T2DM-nMCI, and these changes were correlated with the Mini-Mental State Examination (MMSE) score. Further machine learning data showed that increases in PRNP, CRHBP, VCP, and rGSK-3ß(T/S9) (ratio of total to serine-9-phosphorylated glycogen synthase kinase-3ß) had the greatest power to identify mild cognitive decline in T2DM patients.

The relationship between the main leaf traits and photosynthetic physiological characteristics of Phragmites australis under different habitats of a salt marsh in Qinwangchuan, China.

Plant leaf morphological and photosynthetic physiological characteristics are key functional traits in the adaptability of plants to heterogeneous environments. Analysis of the correlation between leaf morphological traits and photosynthetic physiological characteristics of salt marsh plants is helpful to deepen our understanding of how salt marsh plants adjust their leaf structure and function to adapt to their environment. However, there have been few studies on the relationship between leaf morphology and photosynthetic physiological characteristics of plants in inland salt marshes under a habitat gradient. A Phragmites australis community was divided into three plots based on differences in the wetland habitat conditions: a remote water area (plot I, 400-550 m from the water margin), a middle water area (plot II, 200-350 m from the water margin) and a near water area (plot III, 0-150 m from the water margin). The relationship between leaf morphological traits and photosynthetic physiological parameters of P. australis in heterogeneous habitats was studied. The results showed that as the habitat conditions changed from plot I to plot III, the soil characteristics, above-ground characteristics of the community and the photosynthetically active radiation changed significantly (P < 0.05). Besides, there was a highly significant positive correlation (P < 0.01) between leaf dry weight (LDW) and net photosynthetic rate (P n), the effective quantum yield of PSII photochemistry (Y(II), actual photochemical efficiency of PSII) and photochemical quenching (QP); and between leaf area and P n, Y(II) and QP in the three habitats. Moreover, in plot I, P. australis tended to have small and thick leaves with a low LDW and specific leaf area. In plot III, leaves were large and thin to adapt to the change in habitat conditions. This study provides a scientific theoretical basis for understanding the ecological adaptation strategies of plants in the harsh environment of an inland salt marsh and the conservation and management of wetland plants.

Perspectives of herbs and their natural compounds, and herb formulas on treating diverse diseases through regulating complicated JAK/STAT signaling.

JAK/STAT signaling pathways are closely associated with multiple biological processes involved in cell proliferation, apoptosis, inflammation, differentiation, immune response, and epigenetics. Abnormal activation of the STAT pathway can contribute to disease progressions under various conditions. Moreover, tofacitinib and baricitinib as the JAK/STAT inhibitors have been recently approved by the FDA for rheumatology disease treatment. Therefore, influences on the STAT signaling pathway have potential and perspective approaches for diverse diseases. Chinese herbs in traditional Chinese medicine (TCM), which are widespread throughout China, are the gold resources of China and have been extensively used for treating multiple diseases for thousands of years. However, Chinese herbs and herb formulas are characterized by complicated components, resulting in various targets and pathways in treating diseases, which limits their approval and applications. With the development of chemistry and pharmacology, active ingredients of TCM and herbs and underlying mechanisms have been further identified and confirmed by pharmacists and chemists, which improved, to some extent, awkward limitations, approval, and applications regarding TCM and herbs. In this review, we summarized various herbs, herb formulas, natural compounds, and phytochemicals isolated from herbs that have the potential for regulating multiple biological processes via modulation of the JAK/STAT signaling pathway based on the published work. Our study will provide support for revealing TCM, their active compounds that treat diseases, and the underlying mechanism, further improving the rapid spread of TCM to the world.

Integrated analyses of brain and platelet omics reveal their common altered and driven molecules in Alzheimer's disease.

Platelets may serve as a perfect peripheral source for exploring diagnostic biomarkers for Alzheimer's disease (AD); however, the molecular linkage between platelet and the brain is missing. To find the common altered and driving molecules in both brain and the platelet, we performed an integrated analysis of our platelet omics and brain omics reported in the literature, and analyzed their correlations with AD-specific pathology and cognitive impairment. By integrating the gene and protein expression profiles from 269 AD patients, we deduced 239 differentially expressed proteins (DEPs) appeared in both brain and the platelet, and 70.3% of them had consistent changes. Further analysis demonstrated that the altered brain and peripheral regulations were pinpointed into 10 imbalanced pathways. We also found that 117 DEPs, including ADAM10, were closely associated to the AD-specific ß-amyloid and tau pathologies; and the changes of IDH3B and RTN1 had a potential diagnostic value for cognitive impairment analyzed by machine learning. Finally, we identified that HMOX2 and SERPINA3 could serve as driving molecules in neurodegeneration, and they were increased and decreased in AD patients, respectively. Together, this integrated brain and platelet omics provides a valuable resource for establishing efficient peripheral diagnostic biomarkers and potential therapeutic targets for AD.

Infralimbic medial prefrontal cortex signalling to calbindin 1 positive neurons in posterior basolateral amygdala suppresses anxiety- and depression-like behaviours.

Generalization is a fundamental cognitive ability of organisms to deal with the uncertainty in real-world situations. Excessive fear generalization and impaired reward generalization are closely related to many psychiatric disorders. However, the neural circuit mechanism for reward generalization and its role in anxiety-like behaviours remain elusive. Here, we found a robust activation of calbindin 1-neurons (Calb 1) in the posterior basolateral amygdala (pBLA), simultaneous with reward generalization to an ambiguous cue after reward conditioning in mice. We identify the infralimbic medial prefrontal cortex (IL) to the pBLACalb1 (Calb 1 neurons in the pBLA) pathway as being involved in reward generalization for the ambiguity. Activating IL-pBLA inputs strengthens reward generalization and reduces chronic unpredictable mild stress-induced anxiety- and depression-like behaviours in a manner dependent on pBLACalb1 neuron activation. These findings suggest that the IL-pBLACalb1 circuit could be a target to promote stress resilience via reward generalization and consequently ameliorate anxiety- and depression-like behaviours.

[Microbial Community Structure of Activated Sludge for Total Nitrogen Upgrading Project].

The activated sludge of a biochemical unit (WLK_OD) and an advanced denitrification unit (WLK_AD) were collected from a municipal wastewater treatment plant (WWTP), in which the TN concentration of effluent was less than 1.5 mg·L-1, and their microbial community structure and function profiles were analyzed using 16S rRNA gene high-throughput sequencing. The microorganisms in WLK_AD had lower evenness compared with that in WLK_OD, which was attributed to environmental selection. Furthermore, PCoA revealed that different incoming wastewaters had an impact on microbial community structure. At the phylum level, Proteobacteria (70.11%) was enriched in WLK_AD. At the genus level, Thauera, Flavobacterium, Hydrogenophaga, and Zoogloea served as distinct-dominant denitrifying bacteria in WLK_AD; however, Trichococcus (3.50%) and Terrimonas (1.10%) were enriched in WLK_OD. Through the comparison between groups (P<0.05), the biomarkers detected in each WWTP were different. Furthermore, the results of the co-occurrence network showed that the bacteria from module I had a higher proportion in WLK_AD; the bacteria from module II had a higher proportion in WLK_OD, and they were common microorganisms in WWTPs, implying that wastewater environments drpve the differences in the microbial community structure. Among the types of environmental parameters, the removal efficiency of COD and TN had the greatest impact on the microbial community by the RDA. The removal efficiency of COD was positively correlated with the dominant bacteria from WLK_OD, such as Saccharibacteria, Thermomarinilinea, Terrimonas, and Comamonas; the removal efficiency of TN was positively correlated with the denitrifying bacteria from WLK_AD, such as Dokdonella, Thauera, Flavobacterium, and Zoogloea. WLK_AD was enriched with Novosphingobium, Dokdonella, Thauera, and Sphingomonas, which synergistically removed TN, leading to the TN of the effluent being less than 1.5 mg·L-1. Moreover, based on the results of function prediction, WLK_AD had a higher proportion of genes that could code the denitrification enzymes.

P301S-hTau acetylates KEAP1 to trigger synaptic toxicity via inhibiting NRF2/ARE pathway: A novel mechanism underlying hTau-induced synaptic toxicities.

BACKGROUND: Human Tau (hTau) accumulation and synapse loss are two pathological hallmarks of tauopathies. However, whether and how hTau exerts toxic effects on synapses remain elusive. METHODS: Mutated hTau (P301S) was overexpressed in the N2a cell line, primary hippocampal neurons and hippocampal CA3. Western blotting and quantitative polymerase chain reaction were applied to examine the protein and mRNA levels of synaptic proteins. The protein interaction was tested by co-immunoprecipitation and proximity ligation assays. Memory and emotion status were evaluated by a series of behavioural tests. The transcriptional activity of nuclear factor-erythroid 2-related factor 2 (NRF2) was detected by dual luciferase reporter assay. Electrophoresis mobility shift assay and chromosome immunoprecipitation were conducted to examine the combination of NRF2 to specific anti-oxidative response element (ARE) sequences. Neuronal morphology was analysed after Golgi staining. RESULTS: Overexpressing P301S decreased the protein levels of post-synaptic density protein 93 (PSD93), PSD95 and synapsin 1 (SYN1). Simultaneously, NRF2 was decreased, whereas Kelch-like ECH-associated protein 1 (KEAP1) was elevated. Further, we found that NRF2 could bind to the specific AREs of DLG2, DLG4 and SYN1 genes, which encode PSD93, PSD95 and SYN1, respectively, to promote their expression. Overexpressing NRF2 ameliorated P301S-reduced synaptic proteins and synapse. By means of acetylation at K312, P301S increased the protein level of KEAP1 via inhibiting KEAP1 degradation from ubiquitin-proteasome pathway, thereby decreasing NRF2 and reducing synapse. Blocking the P301S-KEAP1 interaction at K312 rescued the P301S-suppressed expression of synaptic proteins and memory deficits with anxiety efficiently. CONCLUSIONS: P301S-hTau could acetylate KEAP1 to trigger synaptic toxicity via inhibiting the NRF2/ARE pathway. These findings provide a novel and potential target for the therapeutic intervention of tauopathies.

Phosphorylation of Truncated Tau Promotes Abnormal Native Tau Pathology and Neurodegeneration.

Abnormal posttranslational modifications of tau play important roles in mediating neurodegeneration in tauopathies including Alzheimer's disease. Both phosphorylation and truncation are implicated in the pathogenesis of tauopathies. However, whether phosphorylation aggravates truncated tau-induced pathology and neurodegeneration remains elusive. Here, we construct different tau fragments cleaved by delta secretase, with either phosphorylation or non-phosphorylation mimic mutations, and evaluate the contributions of phosphorylation to truncated tau-induced pathological and behavioral alterations in vitro and in vivo through biochemical methods including detergent insoluble tau extraction, western blot, immunofluorescence, flow cytometry, and behavior tests. Our results show that the self-aggregation of phospho-truncated tau is significantly influenced by the domain it contains. N-terminal inhibits, proline-rich domain promotes, and C-terminus have no impact on phospho-truncated tau aggregation. Phosphorylation of truncated tau1-368, which contains the microtubule-binding repeat domain and the proline-rich domain, induces endogenous tau phosphorylation and aggregation. In vivo, phospho-tau1-368 but not non-phospho-tau1-368 leads to a decrease in body weight of C57BL/6 J mice. Intriguingly, although tau1-368-induced anxiety behavior in C57BL/6 J mice is phosphorylation-independent, the recognition memory of mice is impaired by phospho-tau1-368, but not by non-phospho-tau1-368. Immunofluorescence staining shows that overexpressing phospho-tau1-368 results in neuronal loss and gliosis in the hippocampus, while the transmission of tau1-368 is phosphorylation-independent as revealed by the flow cytometry results in vitro and immunofluorescence staining in vivo. Our findings indicate that phosphorylation of truncated tau significantly fosters endogenous tau pathology and neurodegeneration.

Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling.

BACKGROUND: Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer's disease (AD). This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy. METHODS: The primary hippocampal neurons, N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy, which was analysed by Student's two-tailed t-test. The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1 (mTORC1) activity and the vacuolar H+-ATPase (v-ATPase) activity, respectively, which were analysed by One-way ANOVA with post hoc tests. The Western blotting, co-immunoprecipitation and immunofluorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations, as analysed by Student's two-tailed t-test or One-way ANOVA with post hoc tests. The autophagosome formation was detected by immunofluorescence staining and transmission electron microscopy. The amino acids (AA) levels were detected by high performance liquid chromatography (HPLC). RESULTS: We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits. Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1 (PRD-TIA1) and this association significantly increased the intercellular level of amino acids (Leucine, P = 0.0038; Glutamic acid, P = 0.0348; Alanine, P = 0.0037; Glycine, P = 0.0104), with concordant upregulation of mTORC1 activity [phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4EBP1), P < 0.0001; phosphorylated 70 kDa ribosomal protein S6 kinase 1 (p-p70S6K1), P = 0.0001, phosphorylated unc-51-like autophagy-activating kinase 1 (p-ULK1), P = 0.0015] and inhibition of autophagosome formation [microtubule-associated protein light chain 3 II (LC3 II), P = 0.0073; LC3 puncta, P < 0.0001]. As expected, this tau-induced deficit of autophagosome formation in turn aggravated tau accumulation. Importantly, we also found that blocking TIA1 and tau interaction by overexpressing PRD-TIA1, downregulating the endogenous TIA1 expression by shRNA, or downregulating tau protein level by a small proteolysis targeting chimera (PROTAC) could remarkably attenuate tau-induced autophagy impairment. CONCLUSIONS: Our findings reveal that AD-like tau accumulation inhibits autophagosome formation and induces autophagy deficits by activating the TIA1/amino acid/mTORC1 pathway, and thus this work reveals new insight into tau-associated neurodegeneration and provides evidence supporting the use of new therapeutic targets for AD treatment and that of related tauopathies.

Polydatin alleviates DSS- and TNBS-induced colitis by suppressing Th17 cell differentiation via directly inhibiting STAT3.

Inflammatory bowel disease (IBD) is a non-specific chronic intestinal inflammatory disease, often presenting with abdominal pain, diarrhea, bloody stool, anorexia, and body loss. It is difficult to cure completely and a promising treatment is urgently needed. Natural compounds can offer promising chemical agents for treatment of diseases. Polydatin is a natural ingredient extracted from the dried rhizome of Polygonum cuspidatum, which has anti-inflammatory, anti-tumor, and dementia protection activities. The purpose of this study was to evaluate the therapeutic effect of polydatin on IBD and explore its possible mechanism. We found that polydatin could effectively suppress the differentiation of Th17 cells in vitro, but had no effect on the differentiation of Treg cells. Polydatin significantly alleviated colitis induced by dextran sulfate sodium (DSS) and 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) in mice, and dramatically decreased the proportion of Th17 cells in spleen and mesenteric lymph nodes. Mechanism investigations revealed that polydatin specifically inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation by directly binding to STAT3, leading to Th17 cell reduction and thereby alleviating colitis. These findings provide novel insights into the anti-colitis effect of polydatin, which may be a promising drug candidate for the treatment of IBD.