Chemokine ligand 14 correlates with immune cell infiltration in the gastric cancer microenvironment in predicting unfavorable prognosis.

Objective: Gastric cancer (GC) is the world's third-leading cause of cancer-related mortality; the prognosis for GC patients remains poor in terms of a lack of reliable biomarkers for early diagnosis and immune therapy response prediction. Here, we aim to discover the connection between chemokine ligand 14 (CCL14) expression in the gastric tumor microenvironment (TME) and its clinical significance and investigate its correlation with immune cell infiltration. Methods: We assessed CCL14 mRNA expression and its interrelation with tumor-infiltrating immune cells (TILs) using bioinformatics analysis in gastric cancer. CCL14 protein expression, TILs, and immune checkpoints were detected by multiple immunohistochemistry analyses in gastric cancer tissue microarrays. Then, we conducted statistics analysis to determine the association between CCL14-related patient survival and immune cell infiltration (p < 0.05). Results: We found that the CCL14 protein was separately expressed in the carcinoma cells and TILs in stomach cancer tissues. The CCL14 protein was related to tumor differentiation and tumor depth and positively correlated with the presentation of LAG3 and PD-L1 in gastric cancer cells. In addition, the CCL14 protein in the TILs of gastric cancer tissues was related to Lauren's type cells, T cells (CD4+ and CD8+), and CD68+ macrophages in the TME. Kaplan-Meier survival and multivariate analyses showed that the CCL14 expression in gastric cancer cells was an independent prognostic factor. Conclusion: Our study illustrated that CCL14 is a poor prognosis biomarker in gastric cancer, which may be associated with the potential for immunotherapy.

CircBIRC6 facilitates the malignant progression via miR-488/GRIN2D-mediated CAV1-autophagy signal axis in gastric cancer.

Circular RNAs (circRNAs) represent a novel class of non-coding RNAs that play significant roles in tumorigenesis and tumor progression. High-throughput sequencing of gastric cancer (GC) tissues has identified circRNA BIRC6 (circBIRC6) as a potential circRNA derived from the BIRC6 gene, exhibiting significant upregulation in GC tissues. The expression of circBIRC6 is notably elevated in GC patients. Functionally, it acts as a molecular sponge for miR-488, consequently upregulating GRIN2D expression and promoting GC proliferation, migration, and invasion. Moreover, overexpression of circBIRC6 leads to increased GRIN2D expression, which in turn enhances caveolin-1 (CAV1) expression, resulting in autophagy deficiency due to miR-488 sequestration. This cascade of events significantly influences tumorigenesis in vivo. Our findings collectively illustrate that the CircBIRC6-miR-488-GRIN2D axis fosters CAV1 expression in GC cells, thereby reducing autophagy levels. Both circBIRC6 and GRIN2D emerge as potential targets for treatment and independent prognostic factors for GC patients.

WSCD2 Expression: Its Relevance to Tumor-Infiltrating Immune Cells and Glioma Prognosis.

BACKGROUND: Patients with glioma have limited treatment options and experience poor prognoses. Therefore, it is urgently needed to explore new diagnostic and therapeutic targets. OBJECTIVE: This study aimed to investigate the relevance of WSC domain-containing 2 (WSCD2) expression to glioma, clinicopathological characteristics, tumor-infiltrating immune cells (TILs), and patient prognosis. METHODS: We analyzed WSCD2 mRNA expression in glioma tissues and patient survival using the Gene Expression Profiling Interactive Analysis database. Furthermore, the relationship between the expressions of WSCD2 mRNA and TILs in gliomas was evaluated utilizing the Tumor Immune Estimation Resource database. Lastly, we employed multiplex immunohistochemistry to detect the protein expressions of WSCD2 and TILs in glioma tissues. RESULTS: WSCD2 mRNA expression in glioma tissues was lower than that in tissues of benign brain disease. High WSCD2 mRNA expression was also significantly associated with a favorable outcome. Additionally, WSCD2 mRNA expression was correlated with TIL expression in glioma; however, no such relationship was detected between the protein expressions of WSCD2 and TILs in glioma tissues. Cox regression multivariate analysis and Kaplan-Meier survival analysis showed that WSCD2 expression in glioma tissues could be an independent prognostic factor. CONCLUSION: This study highlights the correlation between WSCD2 expression and TILs and demonstrates the prognostic significance of WSCD2 in glioma. Furthermore, our results suggest that WSCD2 may be a potential immunotherapy target in glioma.

Serpin Family A Member 1 Is Prognostic and Involved in Immunological Regulation in Human Cancers.

Serpin family A member 1 (SERPINA1) encodes a protease inhibitor participating in many human diseases, but its value in immunoregulation and prognosis of human cancers remains unclear. In this study, through comprehensive analysis of data from The Cancer Genome Atlas (TCGA) datasets, we found that SERPINA1 was dysregulated in many cancers compared with normal tissues. SERPINA1 expression was significantly associated with prognosis, immune subtype, molecular subtype, immune checkpoint (ICP) genes, tumor mutational burden (TMB), microsatellite instability (MSI), and the estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) score. There was a strong connection between SERPINA1 expression and tumor-infiltrating lymphocytes, and SERPINA1 showed significant relation to gene markers of immune cells in digestive tumors. Fluorescence-based multiplex immunohistochemistry confirmed that SERPINA1 protein expression was related to clinicopathologic features and immune infiltrates in hepatic cancer. This study suggests that SERPINA can potentially serve as a novel biomarker for cancer prognosis and immunotherapy.

Physiological ß-amyloid clearance by the liver and its therapeutic potential for Alzheimer's disease.

Cerebral amyloid-ß (Aß) accumulation due to impaired Aß clearance is a pivotal event in the pathogenesis of Alzheimer's disease (AD). Considerable brain-derived Aß is cleared via transporting to the periphery. The liver is the largest organ responsible for the clearance of metabolites in the periphery. Whether the liver physiologically clears circulating Aß and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Aß42 and 8.9% of Aß40 were removed from the blood when flowing through the liver, and this capacity was decreased with Aß receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Aß levels in both blood and brain interstitial fluid. The chronic decline in hepatic Aß clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Aß burden and cognitive deficits, while enhancing hepatic Aß clearance via LRP-1 overexpression attenuated cerebral Aß deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Aß and regulates brain Aß levels, suggesting that a decline of hepatic Aß clearance during aging could be involved in AD development, and hepatic Aß clearance is a novel therapeutic approach for AD.

KRTCAP2 as an immunological and prognostic biomarker of hepatocellular carcinoma.

Alterations in protein glycosylation affect tumor progression and immune responses in the tumor microenvironment. Keratinocyte-associated protein 2 (KRTCAP2) encodes the corresponding proteins involved in N-glycosylation. The clinical predictive significance and immune role of KRTCAP2 in hepatocellular carcinoma (HCC) largely remain elusive. Combining bioinformatics tools and multiplex immunohistochemistry analysis, we evaluated the KRTCAP2 expression in the HCC tumor microenvironment. The results showed that KRTCAP2 mRNA and protein expression were markedly increased in HCC tissues. Furthermore, high KRTCAP2 expression was an independent predictive factor of unfavorable prognosis in HCC. Moreover, high KRTCAP2 protein expression was associated with a lower proportion of CD8+ T cells and CD68+ macrophages in the stroma region. There was also a lower proportion of CD8+ T cells in the tumor region with high KRTCAP2 protein expression. Specifically, KRTCAP2 expression showed an inverse relationship with programmed cell death ligand-1 in HCC. Analysis of immunophenoscore showed that the low KRTCAP2 expression group had a stronger ability to predict response to immune checkpoint inhibitors. In conclusion, KRTCAP2 had a significant prognostic value for HCC and was correlated with the immune microenvironment. Our findings suggest that KRTCAP2 is a prognostic marker for HCC patients with potential clinical implications for predicting immunotherapeutic responsiveness.

KLHDC8A Expression in Association with Macrophage Infiltration and Oxidative Stress Predicts Unfavorable Prognosis for Glioma.

Background: The tumor immune microenvironment (TME) is associated with cancer progression and immune escape. Although KLHDC8A has been reported in glioma in vitro, the expression and clinical significance of this gene in clinical samples are unknown. Methods: The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases were used to evaluate the mRNA expression level of KLHDC8A and its significance in the glioma TME. Tissue microarray-based multiple immunohistochemical staining was conducted to determine KLHDC8A protein levels and characterize the immune signature of tumor-infiltrating immune cells in gliomas. Results: Tumor cells and tumor-associated macrophages expressed KLHDC8A. The expression of KLHDC8A was higher in glioma tissues than in normal brain tissues and was associated with patient clinical characteristics. Gliomas exhibited a high abundance of macrophages, neutrophils, regulatory T cells, and the immune checkpoint PD-L1, as well as high KLHDC8A expression. Cox regression analysis showed that KLHDC8A+CD68+ macrophages and KLHDC8A predicted unfavorable survival in patients with glioma. Finally, protein-protein interaction network analysis showed that the KLHDC8A expression was associated with hypoxia and oxidative stress. Conclusions: KLHDC8A is a potential marker for the clinical diagnosis of glioma. The immune characteristics of macrophages play a crucial role in predicting patients with glioma, providing a new avenue for targeted glioma therapy.

TP53I13 promotes metastasis in glioma via macrophages, neutrophils, and fibroblasts and is a potential prognostic biomarker.

Background: TP53I13 is a protein coding tumor suppression gene encoded by the tumor protein p53. Overexpression of TP53I13 impedes tumor cell proliferation. Nevertheless, TP53I13 role and expression in the emergence and progression of glioma (low-grade glioma and glioblastoma) are yet to be identified. Thus, we aim to use comprehensive bioinformatics analyses to investigate TP53I13 and its prognostic value in gliomas. Methods: Multiple databases were consulted to evaluate and assess the expression of TP53I13, such as the Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), GeneMANIA, and Gene Expression Profiling Interactive. TP53I13 expression was further explored using immunohistochemistry (IHC) and multiplex immunohistochemistry (mIHC). Through Gene Set Enrichment Analysis (GSEA), the biological functions of TP53I13 and metastatic processes associated with it were studied. Results: The expression of TP53I13 was higher in tumor samples compared to normal samples. In samples retrieved from the TCGA and CGGA databases, high TP53I13 expression was associated with poor survival outcomes. The analysis of multivariate Cox showed that TP53I13 might be an independent prognostic marker of glioma. It was also found that increased expression of TP53I13 was significantly correlated with PRS type, status, 1p/19q codeletion status, IDH mutation status, chemotherapy, age, and tumor grade. According to CIBERSORT (Cell-type Identification by Estimating Relative Subsets of RNA Transcript), the expression of TP53I13 correlates with macrophages, neutrophils, and dendritic cells. GSEA shows a close correlation between TP53I13 and p53 signaling pathways, DNA replication, and the pentose phosphate pathway. Conclusion: Our results reveal a close correlation between TP53I13 and gliomas. Further, TP53I13 expression could affect the survival outcomes in glioma patients. In addition, TP53I13 was an independent marker that was crucial in regulating the infiltration of immune cells into tumors. As a result of these findings, TP53I13 might represent a new biomarker of immune infiltration and prognosis in patients with gliomas.

Identifying immune cells-related phenotype to predict immunotherapy and clinical outcome in gastric cancer.

Background: The tumor microenvironment is mainly composed of tumor-infiltrating immune cells (TIICs), fibroblast, extracellular matrix, and secreted factors. TIICs are often associated with sensitivity to immunotherapy and the prognosis of multiple cancers, yet the predictive role of individual cells on tumor prognosis is limited. Methods: Based on single-sample gene set enrichment analysis, we combined three Gene Expression Omnibus (GEO) cohorts to build a TIIC model for risk stratification and prognosis prediction. The performance of the TIIC model was validated using our clinical cohort and the TCGA cohort. To assess the predictive power of the TIIC model for immunotherapy, we plotted the receiver operating characteristic curve with the IMvigor210 and GSE135222 cohorts. Results: Chemokines, tumor-infiltrating immune cells, and immunomodulators differed between the two TIIC groups. The TIIC model was vital for predicting the outcome of immunotherapy. In our clinical samples, we verified that the expression levels of PD-1 and PD-L1 were higher in the low TIIC score group than in the high TIIC score group, both in the tumor and stroma. Conclusions: Collectively, the TIIC model could provide a novel idea for immune cell targeting strategies in gastric cancer and predict the survival outcome of patients.

NDUFS4 promotes tumor progression and predicts prognosis in gastric cancer.

Gastric cancer ranked third worldwide in terms of mortality. The immediate priority is to search for new prognosticative or therapeutic targets. This research aims to examine the function of the NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4) in the malignant phenotype of gastric carcinoma. We analyzed the correlation between NDUFS4 expression and gastric cancer via bioinformatics analysis and cancer tissue microarray via immunohistochemistry. Also, we detected the phenotype change in gastric cancer cells after NDUFS4 was downregulated. NDUFS4's high expression in gastric cancer tissues showed an association with terminal TNM stage and unfavorable survival. Furthermore, downregulation of NDUFS4 decreased gastric cancer cell proliferation, migration and invasion. Nude mouse models revealed that NDUFS4 promotes tumor growth. This investigation highlights the prognostic role of NDUFS4 in gastric cancer. Our results also creatively ascertained NDUFS4 as a candidate for gastric cancer therapeutic targets.

The Correlations of Plasma Liver-Type Fatty Acid-Binding Protein with Amyloid-ß and Tau Levels in Patients with Alzheimer's Disease.

BACKGROUND: The dysregulation of lipid metabolism plays an important role in the pathogenesis of Alzheimer's disease (AD). Liver-type fatty acid-binding protein (L-FABP, also known as FABP1) is critical for fatty acid transport and may be involved in AD. OBJECTIVE: To investigate whether the FABP1 level is altered in patients with AD, and its associations with levels of amyloid-ß (Aß) and tau in the plasma and cerebrospinal fluid (CSF). METHODS: A cross-sectional study was conducted in a Chinese cohort consisting of 39 cognitively normal controls and 47 patients with AD. The levels of FABP1 in plasma, and Aß and tau in CSF, were measured by enzyme-linked immunosorbent assay (ELISA). A single-molecule array (SIMOA) was used to detect plasma Aß levels. RESULTS: The level of plasma FABP1 was significantly elevated in the AD group (p = 0.0109). Further analysis showed a positive correlation of FABP1 with CSF total tau (t-tau) and phosphorylated tau (p-tau) levels. Besides, plasma FABP1/Aß42 (AUC = 0.6794, p = 0.0071) and FABP1/t-tau (AUC = 0.7168, p = 0.0011) showed fair diagnostic efficacy for AD. When combined with other common AD biomarkers including plasma Aß42, Aß40, and t-tau, both FABP1/Aß42 and FABP1/t-tau showed better diagnostic efficacy than using these biomarkers alone. Among all AUC analyses, the combination of plasma FABP1/t-tau and Aß42 had the highest diagnostic value (AUC = 0.8075, p < 0.0001). CONCLUSION: These findings indicate that FABP1 may play a role in AD pathogenesis and be worthy of further investigation in the future.

Associations of plasma angiostatin and amyloid-ß and tau levels in Alzheimer's disease.

Angiostatin, an endogenous angiogenesis inhibitor generated by the proteolytic cleavage of plasminogen, was recently reported to contribute to the development of Alzheimer's disease (AD). However, whether there are pathological changes in angiostatin levels in individuals with AD dementia is unclear, and whether plasma angiostatin has a relationship with major AD pathological processes and cognitive impairment remains unknown. To examine plasma angiostatin levels in patients with AD dementia and investigate the associations of angiostatin with blood and cerebrospinal fluid (CSF) AD biomarkers, we conducted a cross-sectional study including 35 cognitively normal control (CN) subjects and 59 PiB-PET-positive AD dementia patients. We found that plasma angiostatin levels were decreased in AD dementia patients compared to CN subjects. Plasma angiostatin levels were negatively correlated with plasma Aß42 and Aß40 levels in AD dementia patients and positively correlated with CSF total tau (t-tau) levels and t-tau/Aß42 in AD dementia patients with APOE-ε4. In addition, plasma angiostatin levels had the potential to distinguish AD from CN. These findings suggest a link between angiostatin and AD pathogenesis and imply that angiostatin might be a potential diagnostic biomarker for AD.

Effects of Chemotherapy on Neuroinflammation, Neuronal Damage, Neurogenesis, and Behavioral Performance in Bone Marrow Transplantation Recipient Mice.

As bone marrow transplant (BMT) is gradually applied to the study of central nervous system (CNS) disease, it is needed to investigate the proper dose of chemotherapy to eradicate bone marrow cells while bringing little damage to brain. In the present study, we established a BMT model with varied busulfan and cyclophosphamide (Bu-Cy) dosages. The recipient mice's chimera rate, neuronal death, neuroinflammation, and behavioral functions were all investigated. Chimerism of peripheral blood cells was shown to rise with Bu-Cy treatment doses, with 60.7% in the Bu(20 mg/kg)/Cy(100 mg/kg) group and 93.0% in the Bu(35 mg/kg)/Cy(100 mg/kg) group. Recipients with Bu(35 mg/kg)/Cy(100 mg/kg) therapy had brain injury, increased neuroinflammation, diminished neurogenesis and cognitive abnormalities, whereas animals given a lesser dosage had no such brain damages. Conclusively, considering the chimerism and the possibility to damage brain, we recommend Bu(20 mg/kg)/Cy(100 mg/kg) is the ideal dose in BMT for studying CNS diseases in the C57/BL6 mouse strain.

Holistic View of ALK TKI Resistance in ALK-Positive Anaplastic Large Cell Lymphoma.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase expressed at early stages of normal development and in various cancers including ALK-positive anaplastic large cell lymphoma (ALK+ ALCL), in which it is the main therapeutic target. ALK tyrosine kinase inhibitors (ALK TKIs) have greatly improved the prognosis of ALK+ALCL patients, but the emergence of drug resistance is inevitable and limits the applicability of these drugs. Although various mechanisms of resistance have been elucidated, the problem persists and there have been relatively few relevant clinical studies. This review describes research progress on ALK+ ALCL including the application and development of new therapies, especially in relation to drug resistance. We also propose potential treatment strategies based on current knowledge to inform the design of future clinical trials.

Polysaccharide Krestin Prevents Alzheimer's Disease-type Pathology and Cognitive Deficits by Enhancing Monocyte Amyloid-ß Processing.

Deficits in the clearance of amyloid ß protein (Aß) by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer's disease (AD). Impaired uptake of Aß by dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aß clearance in AD. In the current study, flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin (PSK) on AD-related pathology in vitro and in vivo. We found that PSK, widely used in therapy for various cancers, has the potential to enhance Aß uptake and intracellular processing by human monocytes in vitro. After administration of PSK by intraperitoneal injection, APP/PS1 mice performed better in behavioral tests, along with reduced Aß deposition, neuroinflammation, neuronal loss, and tau hyperphosphorylation. These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aß clearance by blood monocytes and alleviating AD-like pathology.

A Novel Pyroptosis-related Prognostic Model for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the second most lethal malignant tumor because of its significant heterogeneity and complicated molecular pathogenesis. Novel prognostic biomarkers are urgently needed because no effective and reliable prognostic biomarkers currently exist for HCC patients. Increasing evidence has revealed that pyroptosis plays a role in the occurrence and progression of malignant tumors. However, the relationship between pyroptosis-related genes (PRGs) and HCC patient prognosis remains unclear. In this study, 57 PRGs were obtained from previous studies and GeneCards. The gene expression profiles and clinical data of HCC patients were acquired from public data portals. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to establish a risk model using TCGA data. Additionally, the risk model was further validated in an independent ICGC dataset. Our results showed that 39 PRGs were significantly differentially expressed between tumor and normal liver tissues in the TCGA cohort. Functional analysis confirmed that these PRGs were enriched in pyroptosis-related pathways. According to univariate Cox regression analysis, 14 differentially expressed PRGs were correlated with the prognosis of HCC patients in the TCGA cohort. A risk model integrating two PRGs was constructed to classify the patients into different risk groups. Poor overall survival was observed in the high-risk group of both TCGA (p < 0.001) and ICGC (p < 0.001) patients. Receiver operating characteristic curves demonstrated the accuracy of the model. Furthermore, the risk score was confirmed as an independent prognostic indicator via multivariate Cox regression analysis (TCGA cohort: HR = 3.346, p < 0.001; ICGC cohort: HR = 3.699, p < 0.001). Moreover, the single-sample gene set enrichment analysis revealed different immune statuses between high- and low-risk groups. In conclusion, our new pyroptosis-related risk model has potential application in predicting the prognosis of HCC patients.

Serum mBDNF and ProBDNF Expression Levels as Diagnosis Clue for Early Stage Parkinson's Disease.

Parkinson's disease (PD) is one of the most common chronic, progressive, and neurodegenerative diseases characterized clinically by resting tremor, bradykinesia, rigidity, and postural instability. As this disease is usually detected in the later stages, the cure is often delayed, ultimately leading to disability due to the lack of early diagnostic techniques. Therefore, it is of great importance to identify reliable biomarkers with high sensitivity and specificity for the early diagnosis of PD. In this study, we aimed to investigate whether serum expressions of mature brain-derived neurotrophic factor (mBDNF) and proBDNF can serve as biomarkers for the diagnosis of PD at early stage. One hundred and fifty-six patients with limb tremor and/or bradykinesia meeting the inclusion criteria were assigned to either ex-PD group (PD cases) or ex-NPD group (non-PD cases) and then reassigned to either po-PD group (with PD) or po-NPD group (without PD) at 1-year follow-up based on the results of the rediagnoses as performed in accordance with MDS Parkinson's diagnostic criteria. To improve early diagnostic accuracy, grouping (PD group and non-PD group) at initial visit and follow-up was performed differently and independently. Serum mBDNF and proBDNF levels were measured by enzyme-linked immunosorbent assays. The results demonstrated that serum levels of mBDNF and mBDNF/proBDNF were significantly lower in the ex-PD group (19.73 ± 7.31 and 0.09 ± 0.05 ng/ml) as compared with the ex-NPD group (23.47 ± 8.21 and 0.15 ± 0.12 ng/ml) (p < 0.01 for both) and in the po-PD group (19.24 ± 7.20 and 0.09 ± 0.05 ng/ml) as compared with the po-NPD group (25.05 ± 7.67 and 0.16 ± 0.14 ng/ml) (p < 0.01 for both). However, a significantly higher serum level of proBDNF was noted in the ex-PD group (235.49 ± 60.75 ng/ml) as compared with the ex-NPD group (191.75 ± 66.12 ng/ml) (p < 0.01) and in the po-PD group (235.56 ± 60.80 ng/ml) as compared with the po-NPD group (188.42 ± 65.08 ng/ml) (p < 0.01). In conclusion, mBDNF/proBDNF can be used as biomarkers for early stage Parkinson's disease; in addition, mBDNF plus proBDNF has better diagnostic value than mBDNF alone in the diagnosis of PD.

High Selectivity of an α-Conotoxin LvIA Analogue for α3ß2 Nicotinic Acetylcholine Receptors Is Mediated by ß2 Functionally Important Residues.

The α3ß2 and α3ß4 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the central and peripheral nervous systems, playing critical roles in various physiological processes and in such pathologies as addiction to nicotine and other drugs of abuse. α-Conotoxin LvIA, which we previously isolated from Conus lividus, modestly discriminates α3ß2 and α3ß4 rat nAChRs exhibiting a ∼17-fold tighter binding to the former. Here, alanine scanning resulted in two more selective analogues [N9A]LvIA and [D11A]LvIA, the former having a >2000-fold higher selectivity for α3ß2. The determined crystal structures of [N9A]LvIA and [D11A]LvIA bound to the acetylcholine-binding protein (AChBP) were followed by homologous modeling of the complexes with the α3ß2 and α3ß4 nAChRs and by receptor mutagenesis, which revealed Phe106, Ser108, Ser113, and Ser168 residues in the ß2 subunit as essential for LvIA binding. These results may be useful for the design of novel compounds of therapeutic potential targeting α3ß2 nAChRs.

Neurotrophin receptor p75 mediates amyloid ß-induced tau pathology.

Neurofibrillary tangles of hyperphosphorylated tau protein (p-tau) are a key pathological feature of Alzheimer's disease (AD). Tau phosphorylation is suggested to be secondary to amyloid-beta (Aß) accumulation. However, the mechanism by which Aß induces tau phosphorylation in neurons remains unclear. Neurotrophin receptor p75 (p75NTR) is a receptor for Aß and mediates Aß neurotoxicity, implying that p75NTR may mediate Aß-induced tau phosphorylation in AD. Here, we showed that Aß-induced tau hyperphosphorylation and neurodegeneration, including tau phosphorylation, synaptic disorder and neuronal loss, in the brains of both male wild-type (Wt) mice and male P301L transgenic mice (a mouse model of human tauopathy) were alleviated by genetic knockout of p75NTR in the both mouse models. We further confirmed that the activation or inhibition of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase-3ß (GSK3ß) significantly changed Aß/p75NTR-mediated p-tau levels in neurons. Treatment of male P301L mice with soluble p75NTR extracellular domain (p75ECD-Fc), which antagonizes the binding of Aß to p75NTR, suppressed tau hyperphosphorylation. Taken together, our findings suggest that p75NTR meditates Aß-induced tau pathology and is a potential druggable target for AD and other tauopathies.