A Novel Engineering Cell Therapy Platform Mimicking the Immune Thrombocytopenia-Derived Platelets to Inhibit Cytokine Storm in Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a common and highly fatal hyperinflammatory syndrome characterized by the aberrant activation of macrophages. To date, there is a lack of targeted therapies for HLH. It is validated that macrophages in HLH efficiently phagocytose anti-CD41-platelets (anti-CD41-PLTs) from immune thrombocytopenia (ITP) patients in previous research. Hence, the pathological mechanisms of ITP are mimicked and anti-CD41-PLTs are utilized to load the macrophage-toxic drug VP16 to construct macrophage-targetable engineered platelets anti-CD41-PLT-VP16, which is a novel targeted therapy against HLH. Both in vitro and in vivo studies demonstrate that anti-CD41-PLT-VP16 has excellent targeting and pro-macrophage apoptotic effects. In HLH model mice, anti-CD41-PLT-VP16 prevents hemophagocytosis and inhibits the cytokine storm. Mechanistic studies reveal that anti-CD41-PLT-VP16 increases the cytotoxicity of VP16, facilitating precise intervention in macrophages. Furthermore, it operates as a strategic "besieger" in diminishing hyperinflammation syndrome, which can indirectly prevent the abnormal activation of T cells and NK cells and reduce the Ab-dependent cell-mediated cytotoxicity effect. The first platelet-based clinical trial is ongoing. The results show that after treatment with anti-CD41-PLT-VP16, HLH patients have a threefold increase in the overall response rate compared to patients receiving conventional chemotherapy. In conclusion, anti-CD41-PLT-VP16 provides a general insight into hyperinflammation syndrome and offers a novel clinical therapeutic strategy for HLH.

Weekly-specific ambient PM1 before and during pregnancy and the risk of gestational diabetes mellitus.

BACKGROUND: Exposure to fine or respirable particulate matter has been linked to an elevated risk of gestational diabetes mellitus (GDM). However, the association between exposure to particulate matter with an aerodynamic diameter ≤ 1 µm (PM1) and GDM has not been explored. METHODS: We conducted a cohort study involving 60,173 pregnant women from nine hospitals in Beijing, China, from February 2015 to April 2021. Daily concentrations of PM1 and ozone were obtained from a validated spatiotemporal artificial intelligence model. We used a modified Poisson regression combined with distributed lag models to estimate the association between weekly-specific PM1 exposure and the risk of GDM after adjusting for individual-level covariates. RESULTS: Among the 51,299 pregnant women included in the final analysis, 4008 were diagnosed with GDM. Maternal exposure to PM1 during preconception and gestational periods was generally associated with an increased risk of GDM. The most pronounced associations were identified during the 12th week before pregnancy, the 5th-8th weeks of the first trimester, and the 23rd-24th weeks of the second trimester. Each 10 µg/m3 increase in PM1 was associated with a relative risk of GDM of 1.65 (95 % CI: 1.59, 1.72) during the preconception period, 1.67 (95 % CI: 1.61, 1.73) in the first trimester, 1.52 (95 % CI: 1.47, 1.58) in the second trimester, and 2.54 (95 % CI: 2.45, 2.63) when considering the first and second trimester combined. CONCLUSIONS: Exposure to PM1 before and during pregnancy was associated with an increased risk of GDM, particularly during the 12 weeks before pregnancy and gestational weeks 5-8 and 23-24.

Intramolecular chalcogen bonding activated SuFEx click chemistry for efficient organic-inorganic linking.

SuFEx click chemistry demonstrates remarkable molecular assembly capabilities. However, the effective utilization of alkyl sulfonyl fluoride hubs in SuFEx chemistry, particularly in reactions with alcohols and primary amines, presents considerable challenges. This study pioneers an intramolecular chalcogen bonding activated SuFEx (S-SuFEx) click chemistry employing alkyl sulfonyl fluorides with γ-S as the activating group. The ChB-activated alkyl sulfonyl fluorides can react smoothly with phenols, alcohols, and amines, exhibiting enhanced reactivity compared to SO2F2. Excellent yields have been achieved with all 75 tested substrates. Pioneering the application of S-SuFEx chemistry, we highlight its immense potential in organic-inorganic linking, considering the critical role of interfacial covalent bonding in material fabrication. The S-SuFEx hub 1c, incorporating a trialkoxy silane group has been specifically designed and synthesized for organic-inorganic linking. In a simple step, 1c efficiently anchors various organic compounds onto surfaces of inorganic materials, forming functionalized surfaces with properties such as antibacterial activity, hydrophobicity, and fluorescence.

Mining Alzheimer's disease clinical data: reducing effects of natural aging for predicting progression and identifying subtypes.

Introduction: Because Alzheimer's disease (AD) has significant heterogeneity in encephalatrophy and clinical manifestations, AD research faces two critical challenges: eliminating the impact of natural aging and extracting valuable clinical data for patients with AD. Methods: This study attempted to address these challenges by developing a novel machine-learning model called tensorized contrastive principal component analysis (T-cPCA). The objectives of this study were to predict AD progression and identify clinical subtypes while minimizing the influence of natural aging. Results: We leveraged a clinical variable space of 872 features, including almost all AD clinical examinations, which is the most comprehensive AD feature description in current research. T-cPCA yielded the highest accuracy in predicting AD progression by effectively minimizing the confounding effects of natural aging. Discussion: The representative features and pathogenic circuits of the four primary AD clinical subtypes were discovered. Confirmed by clinical doctors in Tangdu Hospital, the plaques (18F-AV45) distribution of typical patients in the four clinical subtypes are consistent with representative brain regions found in four AD subtypes, which further offers novel insights into the underlying mechanisms of AD pathogenesis.

A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior.

The single nucleotide polymorphism rs13166360, causing a substitution of valine (Val) 147 to leucine (Leu) in the adenylyl cyclase 2 (ADCY2), has previously been associated with bipolar disorder (BD). Here we show that the disease-associated ADCY2 missense mutation diminishes the enzyme´s capacity to generate the second messenger 3',5'-cylic adenosine monophosphate (cAMP) by altering its subcellular localization. We established mice specifically carrying the Val to Leu substitution using CRISPR/Cas9-based gene editing. Mice homozygous for the Leu variant display symptoms of a mania-like state accompanied by cognitive impairments. Mutant animals show additional characteristic signs of rodent mania models, i.e., they are hypersensitive to amphetamine, the observed mania-like behaviors are responsive to lithium treatment and the Val to Leu substitution results in a shifted excitatory/inhibitory synaptic balance towards more excitation. Exposure to chronic social defeat stress switches homozygous Leu variant carriers from a mania- to a depressive-like state, a transition which is reminiscent of the alternations characterizing the symptomatology in BD patients. Single-cell RNA-seq (scRNA-seq) revealed widespread Adcy2 mRNA expression in numerous hippocampal cell types. Differentially expressed genes particularly identified from glutamatergic CA1 neurons point towards ADCY2 variant-dependent alterations in multiple biological processes including cAMP-related signaling pathways. These results validate ADCY2 as a BD risk gene, provide insights into underlying disease mechanisms, and potentially open novel avenues for therapeutic intervention strategies.

From Sea to Science: Coral Aquaculture for Sustainable Anticancer Drug Development.

Marine natural products offer immense potential for drug development, but the limited supply of marine organisms poses a significant challenge. Establishing aquaculture presents a sustainable solution for this challenge by facilitating the mass production of active ingredients while reducing our reliance on wild populations and harm to local environments. To fully utilize aquaculture as a source of biologically active products, a cell-free system was established to target molecular components with protein-modulating activity, including topoisomerase II, HDAC, and tubulin polymerization, using extracts from aquaculture corals. Subsequent in vitro studies were performed, including MTT assays, flow cytometry, confocal microscopy, and Western blotting, along with in vivo xenograft models, to verify the efficacy of the active extracts and further elucidate their cytotoxic mechanisms. Regulatory proteins were clarified using NGS and gene modification techniques. Molecular docking and SwissADME assays were performed to evaluate the drug-likeness and pharmacokinetic and medicinal chemistry-related properties of the small molecules. The extract from Lobophytum crassum (LCE) demonstrated potent broad-spectrum activity, exhibiting significant inhibition of tubulin polymerization, and showed low IC50 values against prostate cancer cells. Flow cytometry and Western blotting assays revealed that LCE induced apoptosis, as evidenced by the increased expression of apoptotic protein-cleaved caspase-3 and the populations of early and late apoptotic cells. In the xenograft tumor experiments, LCE significantly suppressed tumor growth and reduced the tumor volume (PC3: 43.9%; Du145: 49.2%) and weight (PC3: 48.8%; Du145: 7.8%). Additionally, LCE inhibited prostate cancer cell migration, and invasion upregulated the epithelial marker E-cadherin and suppressed EMT-related proteins. Furthermore, LCE effectively attenuated TGF-ß-induced EMT in PC3 and Du145 cells. Bioactivity-guided fractionation and SwissADME validation confirmed that LCE's main component, 13-acetoxysarcocrassolide (13-AC), holds greater potential for the development of anticancer drugs.

Construction of a circadian rhythm-relevant gene signature for hepatocellular carcinoma prognosis, immunotherapy and chemosensitivity prediction.

Aims: This study explored the molecular and biologic mechanisms underlying the association between circadian rhythm disorders (CRD) and increased risk for hepatocellular carcinoma (HCC). Background: CRD are linked to increased risk for HCC, but the molecular and biologic mechanisms underlying this association are limited.ObjectiveThe study constructed and validated a CRD related gene model as an independent prognostic factor for HCC, providing insight into the molecular mechanisms linking CRD to increased HCC risk and identifying potential indicators for the efficacy of immunotherapy and anticancer drugs. This helps provide important clues for personalized treatment strategies for HCC patients. Methods: Gene sets correlated with circadian rhythm were obtained from the Molecular Signatures Database (MSigDB) to intersect with differentially expressed genes (DEGs) between tumor samples and control samples in The Cancer Genome Atlas (TCGA) and HCCDB18 from Hepatocellular Carcinoma Cell DataBase (HCCDB). The CRD related gene model was developed by univariate Cox and stepwise multivariate analysis. Immune checkpoint blockade (ICB) therapy and anticancer drugs were analyzed using the tumor immune dysfunction and exclusion (TIDE) and pRRophetic, respectively. Seurat determined the cell type of HCC by analyzing single-cell data, and malignant cells were identified using Copykat. To detect the mRNA levels of genes in the CRD related gene model, quantitative real-time polymerase chain reaction (qRT-PCR) was carried out. Results: The activity of circadian rhythm in HCC tissue was significantly lower than that in control tissue. Subsequently, EZH2, IMPDH2, TYMS and SERPINE1 were selected to construct the CRD related gene model, which was an independent factor for HCC prognosis. Notably, low-risk patients had lower levels of immune cell infiltration and lower TIDE scores compared to high-risk patients with HCC, indicating that patients with a low risk may derive more benefit from immunotherapy. IMPDH2, TYMS and SERPINE1 expressed significantly higher in malignant cells than in benign epithelial cells. Conclusions: This study presents a CRD related gene model to reveal the molecular perspective of the dependent mechanism of the association between CRD and cancer, which provides a potential indicator for understanding the preclinical efficacy of ICB and anticancer drugs.

PKCδ serves as a potential biomarker and therapeutic target for microglia-mediated neuroinflammation in Alzheimer's disease.

INTRODUCTION: To investigate the role of a novel type of protein kinase C delta (PKCδ) in the neuroinflammation of Alzheimer's disease (AD). METHODS: We analyzed PKCδ and inflammatory cytokines levels in cerebrospinal fluid (CSF) of AD and normal controls, as well as their correlations. The cellular expression pattern of PKCδ and the effects of PKCδ modulation on microglia-mediated neuroinflammation were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), western blot, RNA sequencing (RNA-seq), and immunofluorescence staining. RESULTS: PKCδ levels were increased dramatically in the CSF of AD patients and positively correlated with cytokines. PKCδ is expressed mainly in microglia in the brain. Amyloid beta (Aß) stimulation increased PKCδ expression and secretion, which led to upregulation of the nuclear factor kappa B (NF-κB) pathway and overproduction of proinflammatory cytokines. Downregulation or inhibition of PKCδ attenuated Aß-induced microglial responses and improved cognitive function in an AD mouse model. DISCUSSION: Our study identifies PKCδ as a potential biomarker and therapeutic target for microglia-mediated neuroinflammation in AD. HIGHLIGHTS: Protein kinase C delta (PKCδ) levels increase in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), and positively correlate with elevated inflammatory cytokines in human subjects. PKCδ is expressed mainly in microglia in vivo, whereas amyloid beta (Aß) stimulation increases PKCδ expression and secretion, causing upregulation of the nuclear factor kappa B (NF-κB) pathway and production of inflammatory cytokines. Downregulation or inhibition of PKCδ attenuates Aß-enhanced NF-κB signaling and cytokine production in microglia and improves cognitive function in AD mice. PKCδ serves as a potential biomarker and therapeutic target for microglia-mediated neuroinflammation in AD.

[Research Progress on Role of Long Non-Coding RNA in Occurrence and Development of Acute Myeloid Leukemia--Review].

In recent years, the importance of long non-coding RNA (lncRNA) in acute myeloid leukemia (AML) has attracted wide attention. Among them, lncRNAs that play a role in promoting cancer mainly include HOTAIR, UCA1, H19, ITGB2-AS1 and some genes of SNHG family, while in tumor suppression mainly include H22954, NEAT1, SNHG4, LINC01128 , etc. This article reviews the role of lncRNAs in the occurrence and development of AML, as well as those related to AML resistance and prognosis assessment, so as to provide a theoretical basis for the diagnosis and prognosis analysis of AML.

[Responses of radial growth of Fraxinus mandshurica from different provenances to climate at Maoershan in Northeast China]. / 东北地区帽儿山种源实验林区不同种源水曲柳径向生长对气候的响应.

To understand the responses of radial growth of Fraxinus mandshurica from different provenances to climatic factors, we used the dendrochronological method to establish the standard chronologies of F. mandshurica from 20 provenances in Maoershan provenance test forest, and analyzed the differences in radial growth and their correlation with climate factors. The results showed that the overall trend of F. mandshurica chronologies from 20 provenances was generally similar. There were differences in growth amplitude, with the average radial growth of F. mandshurica from Dailing, Lushuihe and Sanchazi being the highest. The radial growth of F. mandshurica from 20 provenances was significantly positively correlated with the highest temperature in July and the average temperature in July except for Huinan. The radial growth of F. mandshurica from 14 provenances was significantly positively correlated with the precipitation in August. The radial growth of F. mandshurica was constrained by temperature and precipitation during the growing season. There was difference in radial growth among F. mandshurica from different provenances under drought stress. F. mandshurica from Wangqing, Dailing, and Hailin had stronger resistance to drought, while that from Wandianzi, Zhanhe, and Xinglong had better recovery ability after drought.

Development and validation of a nomogram to predict risk of septic cardiomyopathy in the intensive care unit.

The aim of this study was to develop a simple but effective nomogram to predict risk of septic cardiomyopathy (SCM) in the intensive care unit (ICU). We analyzed data from patients who were first admitted to the ICU for sepsis between 2008 and 2019 in the MIMIC-IV database, with no history of heart disease, and divided them into a training cohort and an internal validation cohort at a 7:3 ratio. SCM is defined as sepsis diagnosed in the absence of other cardiac diseases, with echocardiographic evidence of left (or right) ventricular systolic or diastolic dysfunction and a left ventricular ejection fraction (LVEF) of less than 50%. Variables were selected from the training cohort using the Least Absolute Shrinkage and Selection Operator (LASSO) regression to develop an early predictive model for septic cardiomyopathy. A nomogram was constructed using logistic regression analysis and its receiver operating characteristic (ROC) and calibration were evaluated in two cohorts. A total of 1562 patients participated in this study, with 1094 in the training cohort and 468 in the internal validation cohort. SCM occurred in 13.4% (147 individuals) in the training cohort, 16.0% (75 individuals) in the internal validation cohort. After adjusting for various confounding factors, we constructed a nomogram that includes SAPS II, Troponin T, CK-MB index, white blood cell count, and presence of atrial fibrillation. The area under the curve (AUC) for the training cohort was 0.804 (95% CI 0.764-0.844), and the Hosmer-Lemeshow test showed good calibration of the nomogram (P = 0.288). Our nomogram also exhibited good discriminative ability and calibration in the internal validation cohort. Our nomogram demonstrated good potential in identifying patients at increased risk of SCM in the ICU.

Efficacy and prognostic value of peripheral blood CD4+ T cells and serum IL-6 and IL-8 in tuberculous meningitis.

Objective: To investigate the value of peripheral blood clusters of differentiation 4 (CD4+) T-lymphocyte (T cells) count and serum interleukin-6 (IL-6) and interleukin-8 (IL-8) in the treatment and prognosis of tuberculous meningitis (TBM). Methods: Sixty-five patients with TBM were prospectively included in the observation group. Sixty-five patients with pulmonary TB and a group of 65 healthy individuals served as the control groups. The differences in peripheral blood CD4+ T-cell count, serum IL-6, and IL-8 levels were compared, and changes in these indices after anti-TB treatment in the observation group were analysed. The observation group was divided into effective and ineffective groups based on their response after 24 weeks of anti-TB treatment. The study also evaluated the influence of peripheral blood CD4+ T-cell count, serum IL-6, and IL-8 levels on the adverse prognosis of TBM during anti-TB treatment. Results: Before treatment, the CD4+ T-cell count in the peripheral blood of the observation group was lower than in both the control and healthy groups, and serum IL-6 and IL-8 levels were higher than in the control group (P < 0.001). After 24 weeks of anti-TB treatment, the CD4+ T-cell count in the peripheral blood of the observation group increased, whereas the levels of IL-6 and IL-8 decreased significantly (P < 0.001). The levels of CD4+ T cells and IL-6 in the peripheral blood of patients before treatment were identified as independent factors influencing the efficacy of anti-TB treatment (odds ratio [OR] = 0.989, 95 % confidence interval [CI]: 0.980-0.997; OR = 1.010, 95 % CI: 1.003-1.017). Conclusion: In patients with TBM, the CD4+ T-cell count in the peripheral blood is decreased, whereas serum IL-6 and IL-8 are increased. The combination of CD4+ T cells and IL-8 shows a degree of predictive value for the prognosis of anti-TB treatment.

Drought shortens subtropical understory growing season by advancing leaf senescence.

Subtropical forests, recognized for their intricate vertical canopy stratification, exhibit high resistance to extreme drought. However, the response of leaf phenology to drought in the species-rich understory remains poorly understood. In this study, we constructed a digital camera system, amassing over 360,000 images through a 70% throughfall exclusion experiment, to explore the drought response of understory leaf phenology. The results revealed a significant advancement in understory leaf senescence phenology under drought, with 11.75 and 15.76 days for the start and end of the leaf-falling event, respectively. Pre-season temperature primarily regulated leaf development phenology, whereas soil water dominated the variability in leaf senescence phenology. Under drought conditions, temperature sensitivities for the end of leaf emergence decreased from -13.72 to -11.06 days °C-1, with insignificance observed for the start of leaf emergence. Consequently, drought treatment shortened both the length of the growing season (15.69 days) and the peak growth season (9.80 days) for understory plants. Moreover, this study identified diverse responses among intraspecies and interspecies to drought, particularly during the leaf development phase. These findings underscore the pivotal role of water availability in shaping understory phenology patterns, especially in subtropical forests.

Enhancing soil health and strawberry disease resistance: the impact of calcium cyanamide treatment on soil microbiota and physicochemical properties.

Introduction: Continuous strawberry cropping often causes soil-borne diseases, with 20 calcium cyanamide being an effective soil fumigant, pig manure can often be used as soil organic fertilizer. Its impact on soil microorganisms structure, however, remains unclear. Methods: This study investigated the effectiveness of calcium cyanamide and pig manure in treating strawberry soil, specifically against strawberry anthracnose. We examined the physical and chemical properties of the soil and the rhizosphere microbiome and performed a network analysis. Results: Results showed that calcium cyanamide treatment significantly reduces the mortality rate of strawberry in seedling stage by reducing pathogen abundance, while increasing actinomycetes and Alphaproteobacteria during the harvest period. This treatment also enhanced bacterial network connectivity, measured by the average connectivity of each Operational Taxonomic Unit (OTU), surpassing other treatments. Moreover, calcium cyanamide notably raised the levels of organic matter, available potassium, and phosphorus in the soil-key factors for strawberry disease resistance and yield. Discussion: Overall, applying calcium cyanamide to soil used for continuous strawberry cultivation can effectively decrease anthracnose incidence. It may be by changing soil physical and chemical properties and enhancing bacterial network stability, thereby reducing the copy of anthracnose. This study highlights the dual benefit of calcium cyanamide in both disease control and soil nutrient enhancement, suggesting its potential as a valuable tool in sustainable strawberry farming.

Recruitment of beneficial cucumber rhizosphere microbes mediated by amino acid secretion induced by biocontrol Bacillus subtilis isolate 1JN2.

Introduction: At present, the use of beneficial microorganisms to control cucumber Fusarium wilt is a widely used method, and the rhizosphere microecological reset is one of the mechanisms involved. However, how biocontrol strains reshape cucumber rhizosphere microecology remains to be further studied. Methods: The composition changes of cucumber root exudates induced by biocontrol strain 1JN2, the microbial ecology of cucumber rhizosphere and the colonization ability of biocontrol strain 1JN2 in cucumber rhizosphere were analyzed through UHPLC-MS/MS analysis, Illumina high-throughput sequencing and SEM, respectively. Results: First, cucumber plants treated with biocontrol Bacillus 1JN2 reduced the disease severity of Fusarium wilt by 60%. Significant changes in cucumber root exudates were found after 1JN2 inoculation and the contents of four amino acids including glutamine, tryptophan, glycine and glutamic acid were significantly increased. Second, It was found that the bacterial diversity in the rhizosphere of cucumber was significantly increased in both the strain treatment group and the amino acid mixture treatment group, The number of Bacillus was the largest in all dominant populations, exceeded 20% in all treatment groups. The bacteria of Hydrogenispora and Vicinamibacteria were significantly increased after treatment. Discussion: Overall, the results demonstrated that amino acid substances in cucumber root exudates induced by biocontrol strain 1JN2 can shift the cucumber root microenvironment and prevent the occurrence of Fusarium wilt disease.

The potential molecular mechanism underlying gypenoside amelioration of atherosclerosis in ApoE-/- mice: A multi-omics investigation.

Gypenosides (Gyp) are bioactive components of Gynostemma pentaphyllum that have a variety of pharmacological properties. Extracts of G. pentaphyllum have been found to be effective in the reduction of blood sugar and lipids and prevention of atherosclerosis. Here, the functions of Gyp and the mechanisms underlying their effects on atherosclerosis were investigated. Mice were allocated to three groups, namely, the control (C57BL/6), atherosclerosis model (ApoE-/- mice with high-fat diet), and Gyp-treated groups. Differentially expressed mRNAs, miRNAs, circRNA, and differential metabolites among the groups were analyzed. The results showed that "Fatty acid metabolism", "Fatty acid elongation", "Cytokine-cytokine receptor interaction", and "PI3K-Akt signaling pathway", amongst others, were involved in treatment process. Differentially expressed genes, including Fabp1, Apoe, FADS1, ADH1, SYNPO2, and Lmod1were also identified. Mmu-miR-30a and mmu-miR-30e showed reduced expression in atherosclerosis models but were increased following Gyp treatment, suggesting involvement in the effects of Gyp. In addition, chr5:150604177-150608440 were found to interact with mmu-miR-30a and mmu-miR-30e to regulate their abundance. In terms of metabolomics, Gyp may regulate biological processes involving PGD2 and PGJ2, potentially alleviating atherosclerosis. In conclusion, Gyp appeared to have complex effects on atherosclerosis, most of which were positive. These results support the use of Gyp in the treatment of atherosclerosis.

Bifunctional iRGD-Exo-DOX crosses the blood-brain barrier to target central nervous system lymphoma.

Central nervous system lymphoma (CNSL) is a type of hematological tumor. Treatment of CNSL is difficult due to the existence of the blood-brain barrier (BBB). Here, we used exosomes (Exos), a type of extracellular vesicle, and iRGD to construct a new drug carrier system and use it to load doxorubicin (DOX). The results of in vitro and in vivo experiments showed that the iRGD-Exo-DOX system can efficiently and securely transport DOX through the BBB and target tumor cells. The results suggest that iRGD-Exo-DOX may cross the BBB through brain microvascular endothelial cell-mediated endocytosis. Together, our study indicates an impactful treatment of central nervous system tumors.

P-tau217 correlates with neurodegeneration in Alzheimer's disease, and targeting p-tau217 with immunotherapy ameliorates murine tauopathy.

Neuronal loss is the central issue in Alzheimer's disease (AD), yet no treatment developed so far can halt AD-associated neurodegeneration. Here, we developed a monoclonal antibody (mAb2A7) against 217 site-phosphorylated human tau (p-tau217) and observed that p-tau217 levels positively correlated with brain atrophy and cognitive impairment in AD patients. Intranasal administration efficiently delivered mAb2A7 into male PS19 tauopathic mouse brain with target engagement and reduced tau pathology/aggregation with little effect on total soluble tau. Further, mAb2A7 treatment blocked apoptosis-associated neuronal loss and brain atrophy, reversed cognitive deficits, and improved motor function in male tauopathic mice. Proteomic analysis revealed that mAb2A7 treatment reversed alterations mainly in proteins associated with synaptic functions observed in murine tauopathy and AD brain. An antibody (13G4) targeting total tau also attenuated tau-associated pathology and neurodegeneration but impaired the motor function of male tauopathic mice. These results implicate p-tau217 as a potential therapeutic target for AD-associated neurodegeneration.