Diagnostic Challenges and Emerging Pathogeneses of Selected Glomerulopathies.

Recent progress in glomerular immune complex and complement-mediated diseases have refined diagnostic categories and informed mechanistic understanding of disease development in pediatric patients. Herein, we discuss selected advances in 3 categories. First, membranous nephropathy antigens are increasingly utilized to characterize disease in pediatric patients and include phospholipase A2 receptor (PLA2R), Semaphorin 3B (Sema3B), neural epidermal growth factor-like 1 (NELL1), and protocadherin FAT1, as well as the lupus membranous-associated antigens exostosin 1/2 (EXT1/2), neural cell adhesion molecule 1 (NCAM1), and transforming growth factor beta receptor 3 (TGFBR3). Second, we examine advances in techniques for paraffin and light chain immunofluorescence (IF), including the former's function as a salvage technique and their necessity for diagnosis in adolescent cases of membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) and proliferative glomerulonephritis with monotypic Ig deposits (PGNMID), respectively. Finally, progress in understanding the roles of complement in pediatric glomerular disease is reviewed, with specific attention to overlapping clinical, histologic, and genetic or functional alternative complement pathway (AP) abnormalities among C3 glomerulopathy (C3G), infection-related and post-infectious GN, "atypical" post-infectious GN, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN), and atypical hemolytic uremic syndrome (aHUS).

Integrative analysis of the bladder cancer from a cell cycle NCAM1 perspective at both single cell and bulk resolution.

INTRODUCTION: Bladder cancer (BLCA) is a prevalent and deadly form of urinary cancer, and there is a need for effective therapies, particularly for muscle-invasive bladder cancer (MIBC). Cell cycle inhibitors show promise in restoring control of the cell cycle in BLCA cells, but their clinical prognosis evaluation is limited. METHODS: Transcriptome and scRNA-seq data were collected from the Cancer Genome Atlas Program (TCGA)-BLCA and GSE190888 cohort, respectively. R software and the Seurat package were used for data analysis, including cell quality control, dimensionality reduction, and identification of differentially expressed genes. Genes related to the cell cycle were obtained from the genecards website, and a protein-protein interaction network analysis was performed using cytoscape software. Functional enrichment analysis, immune infiltration analysis, drug sensitivity analysis, and molecular docking were conducted using various tools and packages. BLCA cell lines were cultured and transfected for in vitro experimental assays, including RT-qPCR analysis, and CCK-8 cell viability assays. RESULTS: We identified 32 genes as independent risk or protective factors for BLCA prediction. Functional enrichment analysis revealed their involvement in cell cycle regulation, apoptosis, and various signaling pathways. Using these genes, we developed a nomogram for predicting BLCA survival, which displayed high prognosis stratification efficacy in BLCA patients. Four cell cycle associated key genes identified, including NCAM1, HBB, CKD6, and CTLA4. We also identified the main cell types in BLCA patients and investigated the functional differences between epithelial cells based on their expression levels of key genes. Furthermore, we observed a high positive correlative relationship between the infiltration of cancer-associated fibroblasts and the risk score value. Finally, we conducted in vitro experiments to demonstrate the suppressive role of NCAM1 in BLCA cell proliferation. CONCLUSION: These findings suggest that cell cycle associated genes could serve as potential biomarkers for predicting BLCA prognosis and may represent therapeutic targets for the development of more effective therapies. Hopefully, these findings provide valuable insights into the molecular mechanisms and potential therapeutic targets in BLCA from the perspective of cell cycle. Moreover, NCAM1 was a novel cell proliferation suppressor in the BLCA carcinogenesis.

Cadmium induces physiological and behavioral changes associated with 180 kDa NCAM lower expression and higher polysialic acid, in the African clawed Xenopus laevis tadpoles.

Heavy metals are released into the environment in increasing amounts from different natural and anthropogenic sources. Among them, cadmium contaminates aquatic habitats and represents a threat to Amphibians. To assess the risks of exposure to cadmium in the aquatic environment, we studied the survival rate of early tadpoles of Xenopus laevis under exposure to CdCl2 for 6 days in the concentration range between 0.15 and 150 µM of Cd2+. Tadpoles survived and reached stage 45 before feeding at all concentrations tested except 150 µM Cd2+, which significantly induced death. With an exposure of 15 µM Cd2+, tadpoles' mean body length decreased, heart rate increased, fastest swimming speed decreased, and distance traveled was greater compared to unexposed controls. Additionally, a witness of neuronal normal development, the neural cell adhesion molecules (NCAM) expression, was decreased. Moreover, this cell-surface glycoprotein exhibited higher polysialylation, a post-translational modification capable to reduce cell adhesion properties and to affect organ development. Our study highlights the effects of Cd2+ on a series of parameters including morphology, physiology, and behavior. They emphasize the deregulation of molecular NCAM suggesting this effector is an interesting biomarker to detect cadmic toxicity in early tadpoles.

The effects of induced type I diabetes on developmental regulation of GDNF, NRTN, and NCAM proteins in the dentate gyrus of male rat offspring.

BACKGROUND: Maternal diabetes during pregnancy can affect the neurological development of offspring. Glial cell-derived neurotrophic factor (GDNF), neurturin (NRTN), and neural cell adhesion molecules (NCAM) are three important proteins for brain development. Therefore, this study aimed to investigate the impacts of the mentioned neurotrophic factors in the hippocampal dentate gyrus (DG) of rat offspring born to diabetic mothers. METHODS: Wistar female rats were randomly allocated into diabetic (STZ-D) [(45 mg/kg BW, STZ (Streptozotocin), i.p)], diabetic + NPH insulin (STZ-INS) [(4-6 unit/kg/day SC)], and control groups. The animals in all groups were mated by non-diabetic male rats. Two weeks after birth, male pups from each group were sacrificed and then protein contents of GDNF, NRTN, and NCAM were evaluated using immunohistochemistry. RESULTS: The study found that the expression of GDNF and NRTN in the hippocampus of diabetic rat offspring was significantly higher compared to the diabetic+ insulin and control groups, respectively (P < 0.01, P < 0.001). Additionally, the expression of NCAM was significantly higher in the diabetic group the diabetic+ insulin and control groups (P < 0.01, P < 0.001). CONCLUSIONS: The results of the study revealed that diabetes during pregnancy significantly impacts the distribution pattern of GDNF, NRTN, and NCAM in the hippocampus of rat neonates.

K-Ras(V12) differentially affects the three Akt isoforms in lung and pancreatic carcinoma cells and upregulates E-cadherin and NCAM via Akt3.

K-Ras is the most frequently mutated Ras variant in pancreatic, colon and non-small cell lung adenocarcinoma. Activating mutations in K-Ras result in increased amounts of active Ras-GTP and subsequently a hyperactivation of effector proteins and downstream signaling pathways. Here, we demonstrate that oncogenic K-Ras(V12) regulates tumor cell migration by activating the phosphatidylinositol 3-kinases (PI3-K)/Akt pathway and induces the expression of E-cadherin and neural cell adhesion molecule (NCAM) by upregulation of Akt3. In vitro interaction and co-precipitation assays identified PI3-Kα as a bona fide effector of active K-Ras4B but not of H-Ras or N-Ras, resulting in enhanced Akt phosphorylation. Moreover, K-Ras(V12)-induced PI3-K/Akt activation enhanced migration in all analyzed cell lines. Interestingly, Western blot analyses with Akt isoform-specific antibodies as well as qPCR studies revealed, that the amount and the activity of Akt3 was markedly increased whereas the amount of Akt1 and Akt2 was downregulated in EGFP-K-Ras(V12)-expressing cell clones. To investigate the functional role of each Akt isoform and a possible crosstalk of the isoforms in more detail, each isoform was stably depleted in PANC-1 pancreatic and H23 lung carcinoma cells. Akt3, the least expressed Akt isoform in most cell lines, is especially upregulated and active in Akt2-depleted cells. Since expression of EGFP-K-Ras(V12) reduced E-cadherin-mediated cell-cell adhesion by induction of polysialylated NCAM, Akt3 was analyzed as regulator of E-cadherin and NCAM. Western blot analyses revealed pronounced reduction of E-cadherin and NCAM in the Akt3-kd cells, whereas Akt1 and Akt2 depletion upregulated E-cadherin, especially in H23 lung carcinoma cells. In summary, we identified oncogenic K-Ras4B as a key regulator of PI3-Kα-Akt signaling and Akt3 as a crucial regulator of K-Ras4B-induced modulation of E-cadherin and NCAM expression and localization.

NCAM mimetic peptide P2 synergizes with bone marrow mesenchymal stem cells in promoting functional recovery after stroke.

The neural cell adhesion molecule (NCAM) promotes neural development and regeneration. Whether NCAM mimetic peptides could synergize with bone marrow mesenchymal stem cells (BMSCs) in stroke treatment deserves investigation. We found that the NCAM mimetic peptide P2 promoted BMSC proliferation, migration, and neurotrophic factor expression, protected neurons from oxygen-glucose deprivation through ERK and PI3K/AKT activation and anti-apoptotic mechanisms in vitro. Following middle cerebral artery occlusion (MCAO) in rats, P2 alone or in combination with BMSCs inhibited neuronal apoptosis and induced the phosphorylation of ERK and AKT. P2 combined with BMSCs enhanced neurotrophic factor expression and BMSC proliferation in the ischemic boundary zone. Moreover, combined P2 and BMSC therapy induced translocation of nuclear factor erythroid 2-related factor, upregulated heme oxygenase-1 expression, reduced infarct volume, and increased functional recovery as compared to monotreatments. Treatment with LY294002 (PI3K inhibitor) and PD98059 (ERK inhibitor) decreased the neuroprotective effects of combined P2 and BMSC therapy in MCAO rats. Collectively, P2 is neuroprotective while P2 and BMSCs work synergistically to improve functional outcomes after ischemic stroke, which may be attributed to mechanisms involving enhanced BMSC proliferation and neurotrophic factor release, anti-apoptosis, and PI3K/AKT and ERK pathways activation.

Cell adhesion molecule immobilized gold surfaces for enhanced neuron-electrode interfaces.

To provide a long-term solution for increasing the biocompatibility of neuroprosthetics, approaches to reduce the side effects of invasive neuro-implantable devices are still in need of improvement. Physical, chemical, and bioactive design aspects of the biomaterials are proven to be important for providing proper cell-to-cell, cell-to-material interactions. Particularly, modification of implant surfaces with bioactive cues, especially cell adhesion molecules (CAMs) that capitalize on native neural adhesion mechanisms, are promising candidates in favor of providing efficient interfaces. Within this concept, this study utilized specific CAMs, namely N-Cadherin (Neural cadherin, N-Cad) and neural cell adhesion molecule (NCAM), to enhance neuron-electrode contact by mimicking the cell-to-ECM interactions for improving the survival of cells and promoting neurite outgrowth. For this purpose, representative gold electrode surfaces were modified with N-Cadherin, NCAM, and the mixture (1:1) of these molecules. Modifications were characterized, and the effect of surface modification on both differentiated and undifferentiated neuroblastoma SH-SY5Y cell lines were compared. The findings demonstrated the successful modification of these molecules which subsequently exhibited biocompatible properties as evidenced by the cell viability results. In cell culture experiments, the CAMs displayed promising results in promoting neurite outgrowth compared to conventional poly-l-lysine coated surfaces, especially NCAM and N-Cad/NCAM modified surfaces clearly showed significant improvement. Overall, this optimized approach is expected to provide an insight into the action mechanisms of cells against the local environment and advance processes for the fabrication of alternative neural interfaces.

Pax3 induces target-specific reinnervation through axon collateral expression of PSA-NCAM.

Damaged or dysfunctional neural circuits can be replaced after a lesion by axon sprouting and collateral growth from undamaged neurons. Unfortunately, these new connections are often disorganized and rarely produce clinical improvement. Here we investigate how to promote post-lesion axonal collateral growth, while retaining correct cellular targeting. In the mouse olivocerebellar path, brain-derived neurotrophic factor (BDNF) induces correctly-targeted post-lesion cerebellar reinnervation by remaining intact inferior olivary axons (climbing fibers). In this study we identified cellular processes through which BDNF induces this repair. BDNF injection into the denervated cerebellum upregulates the transcription factor Pax3 in inferior olivary neurons and induces rapid climbing fiber sprouting. Pax3 in turn increases polysialic acid-neural cell adhesion molecule (PSA-NCAM) in the sprouting climbing fiber path, facilitating collateral outgrowth and pathfinding to reinnervate the correct targets, cerebellar Purkinje cells. BDNF-induced reinnervation can be reproduced by olivary Pax3 overexpression, and abolished by olivary Pax3 knockdown, suggesting that Pax3 promotes axon growth and guidance through upregulating PSA-NCAM, probably on the axon's growth cone. These data indicate that restricting growth-promotion to potential reinnervating afferent neurons, as opposed to stimulating the whole circuit or the injury site, allows axon growth and appropriate guidance, thus accurately rebuilding a neural circuit.

Swimming alters some proteins of skeletal muscle tissue in rats with Alzheimer-like phenotype.

OBJECTIVES: Exercise training plays a significant role in preventing the destruction of central nerve neurons and muscle atrophy. The purpose of the present study was to investigate the effect of a period of swimming training on the expression of Neural cell adhesion molecule (NCAM), Semaphorin 3A (SEMA3A), and Profilin-1 (PFN1) proteins in the gastrocnemius muscle of Alzheimer-like phenotype rats. METHODS & MATERIALS: 32 Wistar males were (6 weeks of age) divided into four groups: Healthy Control (HC), Alzheimer-like phenotype's Control (AC), Healthy Training (HT), and Alzheimer-like phenotype's Training (AT). Alzheimer-like phenotypes were induced by beta-amyloid injection in the hippocampus. The training program consisted of 20 swimming sessions. Gastrocnemius muscle was removed after the intervention, and NCAM, SEMA3A, and PFN1 proteins were measured by the immunohistoflorescent method. RESULTS: The results showed that SEMA3A was increased (p = 0.001), and NCAM (p = 0.001), and PFN1 (p = 0.001) were decreased in AC compared to the HC group. Also, the results showed that NCAM (p = 0.001) and Pfn1 (p = 0.002) increased in the HT group compared to HC, and the NCAM (p = 0.001) and Pfn1 (p = 0.002) in AT group compared to AC (p = 0.001) increased significantly, while SEMA3A was reduced in the HT group compared to HC (p = 0.001) and AT group compared to AC (p = 0.001) CONCLUSION: Swimming effectively improves axon regeneration and neuronal formation in motor neurons and, therefore, can be an effective intervention to prevent and control the complications of Alzheimer-like phenotype.

CD56/NCAM mediates cell migration of human NK cells by promoting integrin-mediated adhesion turnover.

Natural killer (NK) cells patrol tissue to mediate lysis of virally infected and tumorigenic cells. Human NK cells are typically identified by their expression of neural cell adhesion molecule (NCAM, CD56), yet, despite its ubiquitous expression on NK cells, CD56 remains a poorly understand protein on immune cells. CD56 has been previously demonstrated to play roles in NK cell cytotoxic function and cell migration. Specifically, CD56-deficient NK cells have impaired cell migration on stromal cells and CD56 is localized to the uropod of NK cells migrating on stroma. Here, we show that CD56 is required for NK cell migration on ICAM-1 and is required for the establishment of persistent cell polarity and unidirectional actin flow. The intracellular domain of CD56 (NCAM-140) is required for its function, and the loss of CD56 leads to enlarged actin foci and sequestration of phosphorylated Pyk2, accompanied by increased size and frequency of activated LFA-1 clusters. Together, these data identify a role for CD56 in regulating human NK cell migration through modulation of actin dynamics and integrin turnover.

The impact of life-long strength versus endurance training on muscle fiber morphology and phenotype composition in older men.

Aging is typically associated with decreased muscle strength and rate of force development (RFD), partly explained by motor unit remodeling due to denervation, and subsequent loss of fast-twitch type II myofibers. Exercise is commonly advocated to counteract this detrimental loss. However, it is unclear how life-long strength versus endurance training may differentially affect markers of denervation and reinnervation of skeletal myofibers and, in turn, affect the proportion and morphology of fast-twitch type II musculature. Thus, we compared fiber type distribution, fiber type grouping, and the prevalence of atrophic myofibers (≤1,494 µm2) in strength-trained (OS) versus endurance-trained (OE) master athletes and compared the results to recreationally active older adults (all >70 yr, OC) and young habitually active references (<30 yr, YC). Immunofluorescent stainings were performed on biopsy samples from vastus lateralis, along with leg press maximal strength and RFD measurements. OS demonstrated similar type II fiber distribution (OS: 52.0 ± 16.4%; YC: 51.1 ± 14.4%), fiber type grouping, maximal strength (OS: 170.0 ± 18.9 kg, YC: 151.0 ± 24.4 kg), and RFD (OS: 3,993 ± 894 N·s-1, YC: 3,470 ± 1,394 N·s-1) as young, and absence of atrophic myofibers (OS: 0.2 ± 0.7%; YC: 0.1 ± 0.4%). In contrast, OE and OC exhibited more atrophic fibers (OE: 1.2 ± 1.0%; OC: 1.1 ± 1.4%), more grouped fibers, and smaller proportion of type II fibers (OE: 39.3 ± 11.9%; OC: 35.0 ± 12.4%) than OS and YC (all P < 0.05). In conclusion, strength-trained master athletes were characterized by similar muscle morphology as young, which was not the case for recreationally active or endurance-trained old. These results indicate that strength training may preserve type II fibers with advancing age in older men, likely as a result of chronic use of high contractile force generation.NEW & NOTEWORTHY Aging is associated with loss of fast-twitch type II myofibers, motor unit remodeling, and grouping of myofibers. This study reveals, for the first time, that strength training preserves neural innervation of type II fibers, resulting in similar myofiber type distribution and grouping in life-long strength-trained master athletes as young moderately active adults. In contrast, life-long endurance-trained master athletes and recreationally active old adults demonstrated higher proportion of type I fibers accompanied by more marked grouping of type I myofibers, and more atrophic fibers compared with strength-trained master athletes and young individuals. Thus, strength training should be utilized as a training modality for preservation of fast-twitch musculature, maximal muscle strength, and rapid force capacity (RFD) with advancing age.

Neuronal MHC-I complex is destabilized by amyloid-ß and its implications in Alzheimer's disease.

BACKGROUNDS: The expression of major histocompatibility complex I (MHC-I) in neurons has recently been shown to regulate neurite outgrowth and synaptic plasticity. However, its contribution to neurodegenerative diseases such as Alzheimer's disease (AD) remains largely unknown. METHODS: In this study, we investigated the relationship between impaired MHC-I-ß2M complex and AD in vitro and human AD samples. Interaction between protein was identified by liquid chromatography-tandem mass spectrometry and confirmed by immunoprecipitation. Single-chain trimer of MHC-I-ß2M was generated to study the effect of stabilization of MHC-I-ß2M complex on NCAM1 signaling. RESULTS: MHC-I is destabilized in the brains of AD patients and neuronal cells treated with oligomeric ß-amyloid (Aß). Specifically, Aß oligomers disassemble the MHC-I-ß2-microglobulin (ß2M) complex, leading to reduced interactions with neural cell adhesion molecule 1 (NCAM1), a novel interactor of neuronal MHC-I, and decreased signaling. Inhibition of MHC-I-ß2M complex destabilization by non-dissociable MHC-I-ß2M-peptide complex restored MHC-I-NCAM1 signaling in neuronal cells. CONCLUSIONS: The current study demonstrated that disruption of MHC-1-NCAM1 signaling by Aß induced disassembly of MHC-I-ß2M complex is involved in the pathophysiology of AD. Moreover, our findings suggest modulation of MHC-I stability may be a potential therapeutic target for restoring synaptic function in AD.

Alterations of Plasmatic Biomarkers of Neurodegeneration in Mucopolysaccharidosis Type II Patients Under Enzyme Replacement Therapy.

Mucopolysaccharidosis type II (MPS II) is a disorder caused by a deficient activity of iduronate-2-sulfatase, a lysosomal enzyme responsible for degrading glycosaminoglycans (GAGs). The abnormal storage of GAGs within lysosomes disrupts cellular homeostasis and leads to a severe symptomatology. Patients present neuropsychiatric impairment characterized by mental retardation and impaired cognition. The aim of this study was to quantify four neurodegeneration biomarkers in plasma: brain-derived neurotrophic factor (BDNF), platelet-derived growth factor (PDGF-AA), neural cell adhesion molecule (NCAM) and cathepsin-D, as well as to identify possible correlations with urinary GAGs in seven patients undergoing treatment with ERT (Elaprase® 0.5 mg/kg of body weight). Patients with both severe and attenuated forms of MPS II showed signs of neurodegeneration in neuroimaging exams. Patients have a decrease in BDNF and PDGF-AA concentrations, and an increase in NCAM level compared to controls. No alterations in cathepsin-D concentration were seen. GAGs levels were higher in patients than in controls, but no significant correlations between GAGs and biomarkers were observed. These results evidence that patients have neurodegeneration and that monitoring these biomarkers might be useful for assessing this process. To this date, this is the first work to analyze these plasmatic markers of neurodegeneration in patients.

Golgi satellites are essential for polysialylation of NCAM and expression of LTP at distal synapses.

The complex cytoarchitecture of neurons poses significant challenges for the maturation of synaptic membrane proteins. It is currently unclear whether locally secreted synaptic proteins bypass the Golgi or whether they traffic through Golgi satellites (GSs). Here, we create a transgenic GS reporter mouse line and show that GSs are widely distributed along dendrites and are capable of mature glycosylation, in particular sialylation. We find that polysialylation of locally secreted NCAM takes place at GSs. Accordingly, in mice lacking a component of trans-Golgi network-to-plasma membrane trafficking, we find fewer GSs and significantly reduced PSA-NCAM levels in distal dendrites of CA1 neurons that receive input from the temporoammonic pathway. Induction of long-term potentiation at those, but not more proximal, synapses is severely impaired. We conclude that GSs serve the need for local mature glycosylation of synaptic membrane proteins in distal dendrites and thereby contribute to rapid changes in synaptic strength.

Bell's palsy was associated with TRPV2 downregulation of Schwann cell by cold stress.

OBJECTIVE: Epidemiological and clinical studies have shown that sharp changes in the ambient temperature are associated with the occurrence and development of Bell's palsy. However, the specific pathogenesis of peripheral facial paralysis remains nebulous. This study investigated the effect of cold stress on transient receptor potential cation channel subfamily V member 2 (TRPV2) secretion by Schwann cells and its role in Bell's palsy. MATERIALS AND METHODS: Schwann cell morphology was observed using transmission electron microscopy (TEM). Cell proliferation, apoptosis and cell cycle were analysed using CCK8 and flow cytometry. ELISA, Reverse transcription-quantitative PCR, western blotting and immunocytochemical fluorescence staining were used to detect the effects of cold stress on TRPV2, neural cell adhesion molecule (NCAM) and nerve growth factor (NGF) expression in Schwann cells. RESULTS: Cold stress resulted in a widening of the intercellular space, and the particles on the membrane showed different degrees of loss. Cold stress may cause Schwann cells to enter a cold dormant state. ELISA, RT-qPCR, western blotting and immunocytochemical fluorescences staining indicated that cold stress inhibited the expression of TRPV2, NCAM, and NGF. CONCLUSIONS: Drastic temperature difference between cold and heat can downregulate TRPV2 and the secretome of Schwann cells. The imbalance of Schwann cell homeostasis under such stress may contribute to nerve signalling dysfunction leading to the development of facial paralysis.

Neuroimmunomodulatory properties of polysialic acid.

Polymeric sialic acid (polysialic acid, polySia) is a remarkable posttranslational modification of only few select proteins. The major, and most prominent polySia protein carrier is the neural cell adhesion molecule NCAM. Here, the key functions of polySia are to regulate interactions of NCAM and to balance cellular interactions in brain development and plasticity. During recent years, however, increasing evidence points towards a role of polySia in the modulation of immune responses. These immunomodulatory functions can be mediated by polySia on proteins other than NCAM, presented either on the cell surface or released into the extracellular space. This perspective review summarizes our current knowledge and addresses major open questions on polySia and polySia receptors in modulating innate immune responses in the brain.

Role of Delta/Notch-like EGF-related receptor in blood glucose homeostasis.

Cell-cell interactions are necessary for optimal endocrine functions in the pancreas. ß-cells, characterized by the expression and secretion of the hormone insulin, are a major constituent of functional micro-organs in the pancreas known as islets of Langerhans. Cell-cell contacts between ß-cells are required to regulate insulin production and glucose-stimulated insulin secretion, which are key determinants of blood glucose homeostasis. Contact-dependent interactions between ß-cells are mediated by gap junctions and cell adhesion molecules such as E-cadherin and N-CAM. Recent genome-wide studies have implicated Delta/Notch-like EGF-related receptor (Dner) as a potential susceptibility locus for Type 2 Diabetes in humans. DNER is a transmembrane protein and a proposed Notch ligand. DNER has been implicated in neuron-glia development and cell-cell interactions. Studies herein demonstrate that DNER is expressed in ß-cells with an onset during early postnatal life and sustained throughout adulthood in mice. DNER loss in adult ß-cells in mice (ß-Dner cKO mice) disrupted islet architecture and decreased the expression of N-CAM and E-cadherin. ß-Dner cKO mice also exhibited impaired glucose tolerance, defects in glucose- and KCl-induced insulin secretion, and decreased insulin sensitivity. Together, these studies suggest that DNER plays a crucial role in mediating islet cell-cell interactions and glucose homeostasis.

Isolation and Differentiation of Neurons and Glial Cells from Olfactory Epithelium in Living Subjects.

The study of psychiatric and neurological diseases requires the substrate in which the disorders occur, that is, the nervous tissue. Currently, several types of human bio-specimens are being used for research, including postmortem brains, cerebrospinal fluid, induced pluripotent stem (iPS) cells, and induced neuronal (iN) cells. However, these samples are far from providing a useful predictive, diagnostic, or prognostic biomarker. The olfactory epithelium is a region close to the brain that has received increased interest as a research tool for the study of brain mechanisms in complex neuropsychiatric and neurological diseases. The olfactory sensory neurons are replaced by neurogenesis throughout adult life from stem cells on the basement membrane. These stem cells are multipotent and can be propagated in neurospheres, proliferated in vitro and differentiated into multiple cell types including neurons and glia. For all these reasons, olfactory epithelium provides a unique resource for investigating neuronal molecular markers of neuropsychiatric and neurological diseases. Here, we describe the isolation and culture of human differentiated neurons and glial cells from olfactory epithelium of living subjects by an easy and non-invasive exfoliation method that may serve as a useful tool for the research in brain diseases.

Schizophrenia as autoimmune disease: Involvement of Anti-NCAM antibodies.

Understanding the etiopathogenesis of schizophrenia has always been an unsolved puzzle for modern medicine. This seems to be due to both disease complexity and lack of sufficient knowledge regarding the biological and non-biological anomalies that exhibit schizophrenia subjects. However, dysregulated immunity is a commonly identified feature in affected individuals. Thus, recently, a hallmark study showed causality relationship between anti-NCAM antibodies and schizophrenia-related behaviors in mice. NCAM plays crucial role in neurodevelopment during early life and neuroplasticity against different stressors during adulthood, and its dysfunction in schizophrenia is increasingly proven. The present review provides the main evidence that support the contribution of autoimmunity and NCAM abnormalities in the development of schizophrenia. Furthermore, it introduces five hypotheses that may explain the mechanism by which anti-NCAM antibodies are produced in the context of schizophrenia: (i) molecular mimicry, (ii) gut dysbiosis, (iii) viral infection, (iv) exposure to environmental pollutants, (v) and NCAM production anomalies.

Rescue of synaptic and cognitive functions in polysialic acid-deficient mice and dementia models by short polysialic acid fragments.

Dysregulated cortical expression of the neural cell adhesion molecule (NCAM) and deficits of its associated polysialic acid (polySia) have been found in Alzheimer's disease and schizophrenia. However, the functional role of polySia in cortical synaptic plasticity remains poorly understood. Here, we show that acute enzymatic removal of polySia in medial prefrontal cortex (mPFC) slices leads to increased transmission mediated by the GluN1/GluN2B subtype of N-methyl-d-aspartate receptors (NMDARs), increased NMDAR-mediated extrasynaptic tonic currents, and impaired long-term potentiation (LTP). The latter could be fully rescued by pharmacological suppression of GluN1/GluN2B receptors, or by application of short soluble polySia fragments that inhibited opening of GluN1/GluN2B channels. These treatments and augmentation of synaptic NMDARs with the glycine transporter type 1 (GlyT1) inhibitor sarcosine also restored LTP in mice deficient in polysialyltransferase ST8SIA4. Furthermore, the impaired performance of polySia-deficient mice and two models of Alzheimer's disease in the mPFC-dependent cognitive tasks could be rescued by intranasal administration of polySia fragments. Our data demonstrate the essential role of polySia-NCAM in the balancing of signaling through synaptic/extrasynaptic NMDARs in mPFC and highlight the therapeutic potential of short polySia fragments to restrain GluN1/GluN2B-mediated signaling.