Soluble Neural Cell Adhesion Molecule Research Articles

Interleukin-8 Predicts Fatigue at 12 Months Post-Injury in Children with Traumatic Brain Injury.

Despite many children experiencing fatigue after childhood brain injury, little is known about the predictors of this complaint. To date, traditional indices of traumatic brain injury (TBI) severity have not predicted reliably persisting fatigue (up to three years post-injury). This study aimed to establish whether persisting fatigue is predicted by serum biomarker concentrations in child TBI. We examined whether acute serum biomarker expression would improve prediction models of 12-month fatigue based on injury severity. Blood samples were collected from 87 children (1-17 years at injury) sustaining mild to severe TBI (Glasgow Coma Scale [GCS] range 3-15; mean 12.43; classified as mild TBI [n = 50, 57%] vs. moderate/severe TBI [n = 37, 43%]), and presenting to the emergency departments (ED) and pediatric intensive care units (PICU) at one of three tertiary pediatric hospitals (Royal Children's Hospital (RCH); Hospital for Sick Children (HSC), Toronto; St Justine Children's Hospital (SJH), Montreal). Six serum biomarker concentrations were measured within 24 h of injury (interleukin-6, interleukin-8 [IL-8], soluble vascular cell adhesion molecule [SVCAM], S100 calcium binding protein B [S100B], neuron specific enolase [NSE], and soluble neural cell adhesion molecule [sNCAM]). Fatigue at 12 months post-injury was measured using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (parent report), classified as present/absent using previously derived cut-points. At 12 months post-injury, 22% of participants experienced fatigue. A model including IL-8 was the best serum biomarker for estimating the probability of children experiencing fatigue at 12 months post-injury. The IL-8 also significantly improved predictive models of fatigue based on severity.

Soluble neural cell adhesion molecule and behavioural recovery in minimally conscious patients undergoing transcranial direct current stimulation

BackgroundTranscranial direct current stimulation (tDCS) is used for therapeutic purpose in severely brain-injured patients. The relationship between the recovery after tDCS and potential biomarkers in plasma has been limitedly investigated in patients with minimal conscious state (MCS). ObjectiveTo investigate soluble neuronal adhesion molecule (sNCAM) plasma levels in relation to tDCS and recovery processes in MCS. MethodssNCAM was measured in plasma before (T−1,T0), during (T1) and after (T2, T3) tDCS sessions in eight patients with a post traumatic etiology and at least one year of chronic state. ResultsWhile sNCAM levels were highly correlated overtime, no significant difference was observed in relation to tDCS. An inverse relation was observed between sNCAM levels at baseline and the tDCS long-lasting effects (T−1, r = −0.852, p = 0.007; T0, r = −0.787, p = 0.020). ConclusionsThis exploratory research suggests the sNCAM levels, potentially associated with tDCS outcomes, as a candidate biomarker of neurobiological after-effects in MCS patients.

Cerebrospinal fluid NCAM levels are modulated by disease-modifying therapies.

Little is known about what leads to recovery between relapses in multiple sclerosis (MS), particularly following treatment. In the past, it has been demonstrated that soluble neural cell adhesion molecule (sNCAM), a putative biomarker of neuroplasticity, increased following steroid treatment in the Cerebrospinal fluid (CSF) of MS subjects undergoing acute relapses. Taking this a step further, we have evaluated the effect of disease-modifying treatment (DMTs) on CSF sNCAM levels in various subtypes of MS. We measured CSF sNCAM levels at baseline and after 12-24months of DMT in 69 patients, 49 relapsing-remitting MS (RRMS), 20 progressive MS(PMS), and 24 healthy controls (HC) using an in-house ELISA. Of this, 31 patients had received natalizumab, 17 mitoxantrone, and 21 fingolimod. Changes in disability were measured using EDSS and disease severity by MSSS. In conjunction, CSF NfL levels were also measured. At baseline, the mean sNCAM level was 268.7ng/mL (SD: 109ng/mL) in MS patients compared with 340.6ng/ml (SD: 139ng/mL) in HC, and PMS had significantly lower sNCAM (239.2ng/mL, SD: 123.0, P=0.019) compared to RRMS (269.4, SD: 127.4, P=0.043). After natalizumab and mitoxantrone treatments, we observed an increase in mean sNCAM. However, in the fingolimod-treated group, mean sNCAM decreased. There was no correlation found with EDSS or MSSS, or NfL levels as a whole. Cerebrospinal fluid sNCAM levels were found to be lower in MS than in HC and the lowest sNCAM levels were found in PMS. Following natalizumab and mitoxantrone treatments, we observed an elevation in sNCAM levels, an effect that was not observed following fingolimod treatment. These changes, however, did not appear to correlate with disability in the short-term or NfL levels.

Plasma levels of soluble NCAM in multiple sclerosis

In multiple sclerosis (MS), several adhesion molecules are involved within the central nervous system in inflammatory and neurodegenerative processes that are associated to progressive disability and increasing brain atrophy. The neural cell adhesion molecule (NCAM) has been suggested to participate in the reparative mechanisms and in the remyelination processes, key issues in MS pathology. We aimed at investigating plasma levels of the seldom investigated soluble (s)NCAM, and as comparison those of intercellular adhesion molecule-1 (sICAM-1) and vascular adhesion molecule-1 (sVCAM-1), and their association with clinical and MRI measures of lesion volumes and of global and regional atrophy. The cross-sectional study was conducted in 85 relapsing-remitting (RR)-MS, 53 progressive (P)-MS patients, and 42 healthy individuals (HI).Correlation of MRI measures with plasma levels of these adhesion molecules were not observed.In the MS and HI groups, sNCAM levels were significantly and positively associated with sVCAM-1 levels. Differently, the correlation between sICAM-1 and sVCAM-1 was observed only in MS patients. sNCAM and sVCAM-1 levels were higher in P-MS compared to HI (P = 0.05 and P = 0.028 respectively). The sVCAM-1 levels differed (P < 0.001) among DMTs groups and HI.The association of sNCAM plasma levels with MS disease, as well as differences in sVCAM-1 levels in patients receiving different DMTs, deserve further investigation.

Changes of neuroprotective factors and immune-related factors in aqueous humor of patients with primary open angle glaucoma

Objective To measure cytokine concentrations in aqueous humor of patients with primary open angle glaucoma (POAG) and cataract. Methods A cross-sectional study was performed under the informed consent of each subject from June to December in 2016 in Daping Hospital.A total of 24 cases of POAG patients served as the experimental group, while 22 cases of age related cataract patients served as control group.Concentrations of basic fibroblast growth factor (bFGF), monocyte chemoattractant protein-1 (MCP-1), brain derived neurotrophic factor (BDNF), soluble intercellular adhesion molecule-1 (sICAM-1), soluble neural cell adhesion molecule (sNCAM), and soluble vascular cell adhesion molecule-1 (sVCAM-1) with Luminex 200 were detected between the two groups.Then the comparison and the correlation analysis were performed between the two groups. Results Concentrations of MCP-1, sVCAM-1 and sNCAM in the experimental group were higher than those in the control group, with significant differences between them (P=0.017, 0.007, 0.001). The concentration of bFGF-2 in the experimental group was significantly lower than that in the control group (P=0.027). There was no significant difference in the expression levels of BDNF and sICAM-1 between the two groups (P>0.05). The expression levels of MCP-1, sICAM-1, sNCAM and sVCAM-1 were significantly associated with each other (all at P<0.05). Conclusions The expression levels of MCP-1, sVCAM-1 and sNCAM are elevated in POAG patients.POAG may be a neurodegenerative disease associated with neuroinflammation. Key words: Primary open angle glaucoma; Aqueous humor; Cytokine; Neurodegeneration

Link between neurodegeneration and trabecular meshwork injury in glaucomatous patients

BackgroundGlaucoma is classified as a neurodegenerative disease. However, the biomarkers of neurodegeneration in the aqueous humour of primary open angle glaucoma (POAG) eyes have not been quantitatively examined yet. In this study, levels of neurodegeneration-related cytokines in the aqueous humour of POAG eyes were measured and compared with those of non-glaucoma (senile cataract) control eyes.MethodsThis cross-sectional study included 24 patients (24 eyes) with POAG and 22 patients (22 eyes) with cataract. Aqueous humour samples were collected before the commencement of phacoemulsification surgery. The concentrations of brain-derived neurotrophic factor (BDNF), cathepsin D, myeloperoxidase (MPO), soluble intercellular adhesion molecule-1 (sICAM-1), soluble neural cell adhesion molecule (sNCAM), soluble vascular cell adhesion molecule-1 (sVCAM-1), and plasminogen activator inhibitor-1 (PAI-1) were measured using the Luminex suspension array technique. The clinical characteristics of the patients were also obtained for correlation analysis.ResultsCompared with the cataract group, the levels of cathepsin D (P < 0.001), sNCAM (P < 0.001) and sVCAM-1 (P = 0.007) were significantly higher in the aqueous humour samples from POAG. The levels of BDNF, sICAM-1, MPO and PAI-1 did not differ among the groups. Mean deviation (MD) values measured by the Humphrey Visual Field Analyzer were significantly associated with levels of cathepsin D (P < 0.001; ρ= − 0.668), sICAM-1 (P = 0.003; ρ= − 0.579), sVCAM-1(P < 0.001; ρ= − 0.695), and PAI-1 (P = 0.007; ρ= − 0.533). The cytokines showed a positive correlation among each other (P < 0.0083).ConclusionThese data suggest that POAG patients had elevated levels of multiple biomarkers of neurodegeneration in the aqueous humour, and these elevated biomarkers may be related to trabecular meshwork injury.Trial registrationThis study was registered in the Chinese Clinical Trial Registry (ChiCTR-OOC-16008516) on May 22, 2016.

The high expressed serum soluble neural cell adhesion molecule, a high risk factor indicating hepatic encephalopathy in hepatocelular carcinoma patients.

To investigate whether the expression of serum soluble neural cell adhesion molecule (sNCAM) is associated with hepatic encephalopathy (HE) in hepatocelular carcinoma (HCC) patients. The Oncomine Cancer Microarray database was used to determine the clinical relevance of NCAM expression in different kinds of human cancers. Sera from 75 HCC cases enrolled in this study were assessed for expression of sNCAM by enzyme linked immunosorbent assay (ELISA). Dependent on the Oncomine Cancer Microarray database analysis, NCAM was down regulated in 10 different kinds of cancer, like bladder cancer, brain and central nervous system cancer, while up-regulated in lung cancer, uterine corpus leiomyoma and sarcoma, compared to normal groups. Puzzlingly, NCAM expression demonstrated no significant difference between normal and HCC groups. However, we found by quantitative ELISA that the level of sNCAM in sera from HCC patients with HE (347.4±151.9 ng/ml) was significantly more up-regulated than that in HCC patients without HE (260.3±104.2 ng/ml), the p-value being 0.008. sNCAM may be an important risk factor of HE in HCC patients, the correlation coefficients was 0.278 (P< 0.05) on rank correlation analysis. This study highlights that up-regulated level of serum sNCAM is associated with HE in HCC patients and suggests that the high expression can be used as an indicator.

Soluble polysialylated NCAM: a novel player of the innate immune system in the lung.

Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing "neutrophil extracellular traps", which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes.

Expression and Localization of Neural Cell Adhesion Molecule and Polysialic Acid during Chick Corneal Development

To assay for expression and localization of neural cell adhesion molecule (NCAM) and polysialic acid (polySia) in the chick cornea during embryonic and postnatal development. Real time quantitative PCR and Western blot analyses were used to determine NCAM expression and polysiaylation in embryonic, hatchling, and adult chick corneas. Immunofluorescence staining for NCAM and polySia was conducted on cryosections of embryonic and adult corneas, whole embryonic corneas, and trigeminal neurons. NCAM and ST8SiaII mRNA transcripts peaked by embryonic day (E)9, remained steady between E10 and E14 and slowly decreased thereafter during embryonic development. Both gene transcripts showed > 190-fold decline in the adult chick cornea compared with E9. In contrast, ST8SiaIV expression gradually decreased 26.5-fold from E6 to E19, increased thereafter, and rose to the early embryonic level in the adult cornea. Western blot analysis revealed NCAM was polysialylated and its expression developmentally changed. Other polysiaylated proteins aside from NCAM were also detected by Western blot analysis. Five NCAM isoforms including NCAM-120, NCAM-180 and three soluble NCAM isoforms with low molecular weights (87-96 kDa) were present in chick corneas, with NCAM-120 being the predominate isoform. NCAM was localized to the epithelium, stroma, and stromal extracellular matrix (ECM) of the embryonic cornea. In stroma, NCAM expression shifted from anterior to posterior stroma during embryonic development and eventually became undetectable in 20-week-old adult cornea. Additionally, both NCAM and polySia were detected on embryonic corneal and pericorneal nerves. NCAM and polySia are expressed and developmentally regulated in chick corneas. Both membrane-associated and soluble NCAM isoforms are expressed in chick corneas. The distributions of NCAM and polySia in cornea and on corneal nerves suggest their potential functions in corneal innervation.

Hepatocellular carcinoma with progenitor cell features distinguishable by the hepatic stem/progenitor cell marker NCAM

We analyzed hepatocellular carcinoma (HCC) with progenitor cell features using hepatic stem/progenitor cell marker neural cell adhesion molecule (NCAM). Approximately 8.3% of the operated HCC cases expressed NCAM, and 22.3% of the HCC patients had soluble NCAM levels >1000ng/ml (the “highly soluble” NCAM group). Soluble NCAM status was a significant independent factor predictive of long-term survival in patients with HCC, and high levels of soluble NCAM were significantly related to intrahepatic metastasis. The 140-kDa NCAM isoform was specifically detected in the “highly soluble” NCAM group of HCC patients andits related signals are potential drug targets for NCAM+ HCC.

Neural cell–cell and cell–substrate adhesion through N-cadherin, N-CAM and L1

In this study neural (N)-cadherin, neural cell adhesion molecule (N-CAM) and L1 proteins and their antibody equivalents were covalently immobilized on a polyethylene-imine (PEI)-coated glass surface to form neuron-adhesive coatings. Impedance sensing and (supplementary) image analysis were used to monitor the effects of these CAMs. Immobilization of high concentrations of both N-cadherin protein and antibody led to good adhesion of neurons to the modified surface, better than surfaces treated with 30.0 and 100.0 µg ml−1 N-CAM protein and antibody. L1 antibody and protein coating revealed no significant effect on neuronal cell–substrate adhesion. In a second series of combinatorial experiments, we used the same antibodies and proteins as medium-additives to inhibit cell–cell adhesion between neurons. Adhesion of neurons cultured on N-cadherin protein or antibody-modified surfaces was lowered by the addition of a soluble N-cadherin protein and antibody to the culturing medium, accelerating neuronal aggregation. The presence of a soluble N-CAM antibody or protein had no effect on the adhesion of neuronal cells on a N-cadherin protein-modified surface. On a N-cadherin antibody-coated surface, the addition of a soluble N-CAM protein led to cell death of neurons after 48 h, while a N-CAM antibody had no effect. In the presence of a soluble N-cadherin protein and antibody the aggregation of neurons was inhibited, both on N-CAM protein and N-CAM antibody-modified surfaces. Neurons cultured on immobilized antibodies were less affected by the addition of soluble CAM blockers than neurons cultured on immobilized proteins, indicating that antibody–protein bonds are more stable compared to protein–protein bonds.

Developmental regulation of neural cell adhesion molecule in human prefrontal cortex

Neural cell adhesion molecule (NCAM) is a membrane-bound cell recognition molecule that exerts important functions in normal neurodevelopment including cell migration, neurite outgrowth, axon fasciculation, and synaptic plasticity. Alternative splicing of NCAM mRNA generates three main protein isoforms: NCAM-180, -140, and -120. Ectodomain shedding of NCAM isoforms can produce an extracellular 105–115 kilodalton soluble neural cell adhesion molecule fragment (NCAM-EC) and a smaller intracellular cytoplasmic fragment (NCAM-IC). NCAM also undergoes a unique post-translational modification in brain by the addition of polysialic acid (PSA)-NCAM. Interestingly, both PSA-NCAM and NCAM-EC have been implicated in the pathophysiology of schizophrenia. The developmental expression patterns of the main NCAM isoforms and PSA-NCAM have been described in rodent brain, but no studies have examined NCAM expression across human cortical development. Western blotting was used to quantify NCAM in human postmortem prefrontal cortex in 42 individuals ranging in age from mid-gestation to early adulthood. Each NCAM isoform (NCAM-180, -140, and -120), post-translational modification (PSA-NCAM) and cleavage fragment (NCAM-EC and NCAM-IC) demonstrated developmental regulation in frontal cortex. NCAM-180, -140, and -120, as well as PSA-NCAM, and NCAM-IC all showed strong developmental regulation during fetal and early postnatal ages, consistent with their identified roles in axon growth and plasticity. NCAM-EC demonstrated a more gradual increase from the early postnatal period to reach a plateau by early adolescence, potentially implicating involvement in later developmental processes. In summary, this study implicates the major NCAM isoforms, PSA-NCAM and proteolytically cleaved NCAM in pre- and postnatal development of the human prefrontal cortex. These data provide new insights on human cortical development and also provide a basis for how altered NCAM signaling during specific developmental intervals could affect synaptic connectivity and circuit formation, and thereby contribute to neurodevelopmental disorders.

Developmental regulation of GABAergic interneuron branching and synaptic development in the prefrontal cortex by soluble neural cell adhesion molecule

Neural cell adhesion molecule, NCAM, is an important regulator of neuronal process outgrowth and synaptic plasticity. Transgenic mice that overexpress the soluble NCAM extracellular domain (NCAM-EC) have reduced GABAergic inhibitory and excitatory synapses, and altered behavioral phenotypes. Here, we examined the role of dysregulated NCAM shedding, modeled by overexpression of NCAM-EC, on development of GABAergic basket interneurons in the prefrontal cortex. NCAM-EC overexpression disrupted arborization of basket cells during the major period of axon/dendrite growth, resulting in decreased numbers of GAD65- and synaptophysin-positive perisomatic synapses. NCAM-EC transgenic protein interfered with interneuron branching during early postnatal stages when endogenous polysialylated (PSA) NCAM was converted to non-PSA isoforms. In cortical neuron cultures, soluble NCAM-EC acted as a dominant inhibitor of NCAM-dependent neurite branching and outgrowth. These findings suggested that excess soluble NCAM-EC reduces perisomatic innervation of cortical neurons by perturbing axonal/dendritic branching during cortical development.

Developmental regulation of GABAergic interneuron branching and synaptic development in the prefrontal cortex by soluble neural cell adhesion molecule

Developmental regulation of GABAergic interneuron branching and synaptic development in the prefrontal cortex by soluble neural cell adhesion molecule

Neural cell adhesion molecule (NCAM) induces neuronal phenotype acquisition in dominant negative MEK1-expressing hippocampal neural progenitor cells

It has been shown that neural cell adhesion molecule (NCAM)-induced neuronal differentiation is extracellular signal-regulated kinase (ERK)-dependent. However, an involvement of the mitogen activated protein kinase (MAPK) kinase (MEK), an upstream kinase of ERK, has not been directly demonstrated in this process. Therefore, we investigated whether the MEK1 plays a critical role in the NCAM-induced neuronal differentiation of hippocampal neural progenitor cells (NPCs). NPCs were transiently transfected with expression plasmids encoding activated or dominant negative (DN) forms of MEK1. The expression of DN MEK1 inhibited neuronal phenotype acquisition and soluble NCAM rescued the defect in the neuronal phenotype acquisition in DN-MEK1-transfected cells, suggesting that NCAM might contribute to the neuronal differentiation via distinct, parallel pathways including the MEK pathway. In cells expressing wild type MEK1 or constitutively active MEK1 on the other hand, the percentage of cells positive for beta-tubulin type III (Tuj1), a marker for early postmitotic neurons, was higher than seen in vector-transfected cells. These results suggest that the activation of MEK1 is required for obtaining neuronal phenotype in NPCs.

Metalloprotease‐induced ectodomain shedding of neural cell adhesion molecule (NCAM)

Transmembrane forms of neural cell adhesion molecule (NCAM140, NCAM180(1)) are key regulators of neuronal development. The extracellular domain of NCAM can occur as a soluble protein in normal brain, and its levels are elevated in neuropsychiatric disorders, such as schizophrenia; however the mechanism of ectodomain release is obscure. Ectodomain shedding of NCAM140, releasing a fragment of 115 kD, was found to be induced in NCAM-transfected L-fibroblasts by the tyrosine phosphatase inhibitor pervanadate, but not phorbol esters. Pervanadate-induced shedding was mediated by a disintegrin metalloprotease (ADAM), regulated by ERK1/2 MAP kinase. In primary cortical neurons, NCAM was shed at high levels, and the metalloprotease inhibitor GM6001 significantly increased NCAM-dependent neurite branching and outgrowth. Moreover, NCAM-dependent neurite outgrowth and branching were inhibited in neurons isolated from a transgenic mouse model of NCAM shedding. These results suggest that regulated metalloprotease-induced ectodomain shedding of NCAM down-regulates neurite branching and neurite outgrowth. Thus, increased levels of soluble NCAM in schizophrenic brain have the potential to impair neuronal connectivity.

Prion Protein Promotes Neurite Outgrowth

Prion protein (PrP) when misfolded is responsible for various neuronal disorders, including Creutzfeld-Jacob disease and "mad cow" disease. The normal physiological functions of PrP are less clear, although a role in cell recognition has been proposed. Santuccione et al . show that PrP and the neural cell adhesion molecule (NCAM) partially colocalize in membrane microdomains called lipid rafts in cultured hippocampal neurons and that the two proteins can be coimmunoprecipitated and chemically cross-linked. The abundance of NCAM140 and NCAM180, but not NCAM120 or the recognition molecule L1, in lipid rafts was reduced in brain homogenates from PrP —/— mice compared with that in wild-type mice. Triton X-100 extraction of cultured neurons to remove soluble, but not lipid raft-associated, proteins indicated that PrP contributed to the stability of NCAM in lipid rafts. Soluble PrP added to cultures from the PrP —/— mice also stabilized NCAM and stimulated the activation of the kinase Fyn. Thus, PrP appears to have a cis (on the same membrane) and trans contribution to recruit (trans) and stabilize (cis) NCAM in lipid rafts and trigger downstream signaling events. Soluble PrP or NCAM activation with antibodies or antibody fragments also induced the redistribution of NCAM into lipid rafts in wild-type cells based on an increase in lipid raft-associated NCAM. However, redistribution and Fyn activation triggered by NCAM antibodies was not observed in PrP —/— cells. A link between Fyn activation and PrP was also supported in vivo, where despite an increase in the overall abundance of Fyn in PrP —/— mouse brain homogenates, there was less phosphorylated (and activated) Fyn. Soluble PrP also triggered neurite outgrowth, and antibodies against PrP inhibited neurite outgrowth, possibly by interfering with cis PrP-NCAM interactions. PrP appears to have a dual role as a trans mediator of NCAM redistribution into lipid rafts and a cis mediator stabilizing NCAM in the lipid rafts and triggering downstream signaling through Fyn to stimulate neurite outgrowth. A. Santuccione, V. Sytnyk, I. Leshchyns'ka, M. Schachner, Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59 fyn and to enhance neurite outgrowth. J. Cell. Biol. 169 , 341-354 (2005). [Abstract] [Full Text]

Neural cell adhesion molecule in human serum. Increased levels in dementia of the Alzheimer type

Memory impairment is a process associated with alterations in neuronal plasticity, synapses formation, and stabilization. As the neural cell adhesion molecule (NCAM) plays a key role in synaptic bond stabilization, we analyzed the usefulness of soluble NCAM isoforms in the diagnosis of patients with dementia of the Alzheimer type (DAT). NCAM was measured in the sera of 70 control subjects and 43 DAT patients (with different severity of cognitive impairment, GDS), employing Western blot and densitometric quantification. LMW-NCAM bands (100–130 kDa) decreased significantly with age independently of sex. DAT patients presented values of LMW-NCAM and HMW-NCAM significantly higher than healthy controls of similar age (higher than 130 kDa). Only LMW-NCAM was associated with GDS. Our results suggest that NCAM could be involved in the pathogenesis of DAT disorder and that serum NCAM levels could be useful as differential diagnostic markers of the disease.

Neural cell adhesion molecule (NCAM) promotes the differentiation of hippocampal precursor cells to a neuronal lineage, especially to a glutamatergic neural cell type.

Rat hippocampal precursor cells isolated from hippocampi of embryonic day 16.5 (E16.5) rat embryos were found to proliferate in the presence of basic fibroblast growth factor. Addition of soluble neural cell adhesion molecule (NCAM) to these precursor cells reduced cell proliferation in a dose dependent manner and enhanced the induction of precursor cells' differentiation to the neuronal lineage. Given these findings that NCAM induces the differentiation of hippocampal precursor cells, we investigated possible effects of NCAM on the expression of basic helix-loop-helix (bHLH) transcription factors during the differentiation. Soluble NCAM upregulated the transcription of bHLH transcription factors, neurogenin1 and NeuroD, but decreased HES5. Western blot analysis showed that NCAM increased the expression levels of CaMKII, p-MAPK, GluR1 and NR1 but decreased p-STAT3. These results support a role for NCAM in the inhibition of proliferation and the induction of neural differentiation of hippocampal neural precursor cells, and act as developmental regulators of the bHLH families, ultimately leading to the generation of glutamatergic neural cell types in the differentiation of hippocampal precursor cells.

Reciprocal actions of NCAM and tPA via a Ras-dependent MAPK activation in rat hippocampal neurons

In an attempt to identify the functions of neural cell adhesion molecule (NCAM) and tissue plasminogen activator (tPA) in hippocampal synaptic plasticity, we investigated the relationship between the two molecules by focusing on mitogen-activated protein kinase (MAPK), an essential enzyme in this process. NCAM clustering in cultured hippocampal neurons transiently induced MAPK within 10 min. Moreover, soluble NCAM also induced a Ras-dependent MAPK activation. Conversely, MAPK activation led to an increase in the expressions of all three isoforms of NCAM. Treatment of neurons with tPA and plasminogen induced a Ras-dependent MAPK activation and tPA-plasmin degradation of NCAM was mediated in a MAPK-dependent manner. Soluble NCAM transiently inhibited tPA mRNA expression levels in a MAPK-dependent manner, while stimulation of MAPK alone induced tPA reduction in cells. These results collectively indicate that NCAM and tPA reciprocally act as important regulators in the modulation of synaptic plasticity via a Ras-MAPK-involved signaling pathway. In turn, MAPK activation may cause tPA degradation or a decrease in expression to promote synaptic plasticity.