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ABSTRACT: Alzheimer's disease (AD) is characterized by the depositions of amyloid-β (Aβ) proteins, resulting in a reduction of choline acetyltransferase (ChAT) activity of AD brain in the early stages of the disease. Several growth factors, including brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF)-1 and glial cell-derived neurotrophic factor (GDNF) are known to protect neuronal cell death in several neurodegenerative both in vitro and in vivo models. In this study, septal neurons were prepared from septal nucleus of embryonic (day 16-17) rat brain and treated with monomeric, oligomeric or fibrillar Aβ(1-42) peptide. Oligomeric Aβ(1-42), (10 μM) was the most potent at sublethal dose. Septal neuron cultures treated with BDNF, IGF-1 or GDNF or co-cultured with genetically modified human neural progenitor cells (hNPCs) secreting these neurotrophic factors (but not allowing contact between the two cell types), were protected from oligomeric Aβ(1-42) peptide-induced cell death, and these trophic factors enhanced cholinergic functions by increasing ChAT expression level. These results indicate the potential of employing transplanted hNPCs for treatment of AD.
Neurochemical Research 09/2011; 37(1):143-52. · 2.24 Impact Factor
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ABSTRACT: Several pieces of evidence suggest that academic examinations fulfill the classical requirement of a psychological stressor. Academic examinations represent a stressful challenge to many students, but studies on examination-dependent corticosteroid response, a sensitive physiological indicator of a stress response, are inconsistent. In addition, several studies showed that music can decrease cortisol and adrenocorticotropic hormone (ACTH) levels, and other studies have found that music also may enhance a variety of cognitive functions, such as attention, learning, communication and memory. The present study investigated cortisol response in saliva of Thai adolescents taking academic examinations and analyzed the differences of the stress response between musician and control subjects. Also, we observed whether the academic examination-dependent corticosteroid response affected learning and memory in the test subjects, which comprised 30 musician and 30 control students, age ranging from 15 to 17 years. Mathematical examinations were used as the stressor. Pre- and post-academic examination saliva cortisol levels were measured including self-estimated stress levels. Results showed that the pre-academic examination saliva cortisol concentrations of the musician group are significantly lower than those of the control group, whereas there is no difference in the stress inventory scores. Interestingly, among students with grade point average (GPA) of >3.50, pre-academic examination cortisol levels are significantly lower in the musician compared with control group. This study suggests that under academic examination-induced stress condition, music training can reduce saliva cortisol level in Thai adolescents.
Neuroscience Letters 10/2010; 487(3):310-2. · 2.11 Impact Factor
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ABSTRACT: The expression of IL-1 is elevated in the CNS in diverse neurodegenerative disorders, including Alzheimer's disease. The hypothesis was tested that IL-1 beta renders neurons vulnerable to degeneration by interfering with BDNF-induced neuroprotection. In trophic support-deprived neurons, IL-1 beta compromised the PI3-K/Akt pathway-mediated protection by BDNF and suppressed Akt activation. The effect was specific as in addition to Akt, the activation of MAPK/ERK, but not PLC gamma, was decreased. Activation of CREB, a target of these signaling pathways, was severely depressed by IL-1 beta. As the cytokine did not influence TrkB receptor and PLC gamma activation, IL-1 beta might have interfered with BDNF signaling at the docking step conveying activation to the PI3-K/Akt and Ras/MAPK pathways. Indeed, IL-1 beta suppressed the activation of the respective scaffolding proteins IRS-1 and Shc; this effect might involve ceramide generation. IL-1-induced interference with BDNF neuroprotection and signal transduction was corrected, in part, by ceramide production inhibitors and mimicked by the cell-permeable C2-ceramide. These results suggest that IL-1 beta places neurons at risk by interfering with BDNF signaling involving a ceramide-associated mechanism.
Neurobiology of aging 10/2008; 29(9):1380-93. · 5.94 Impact Factor
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ABSTRACT: Alzheimer's disease is characterized by the accumulation of neurotoxic amyloidogenic peptide Abeta, degeneration of the cholinergic innervation to the hippocampus (the septohippocampal pathway), and progressive impairment of cognitive function, particularly memory. Abeta is a ligand for the p75 neurotrophin receptor (p75(NTR)), which is best known for mediating neuronal death and has been consistently linked to the pathology of Alzheimer's disease. Here we examined whether p75(NTR) is required for Abeta-mediated effects. Treatment of wild-type but not p75(NTR)-deficient embryonic mouse hippocampal neurons with human Abeta(1-42) peptide induced significant cell death. Furthermore, injection of Abeta(1-42) into the hippocampus of adult mice resulted in significant degeneration of wild-type but not p75(NTR)-deficient cholinergic basal forebrain neurons, indicating that the latter are resistant to Abeta-induced toxicity. We also found that neuronal death correlated with Abeta(1-42) peptide-stimulated accumulation of the death-inducing p75(NTR) C-terminal fragment generated by extracellular metalloprotease cleavage of full-length p75(NTR). Although neuronal death was prevented in the presence of the metalloprotease inhibitor TAPI-2 (tumor necrosis factor-alpha protease inhibitor-2), Abeta(1-42)-induced accumulation of the C-terminal fragment resulted from inhibition of gamma-secretase activity. These results provide a novel mechanism to explain the early and characteristic loss of cholinergic neurons in the septohippocampal pathway that occurs in Alzheimer's disease.
Journal of Neuroscience 05/2008; 28(15):3941-6. · 7.11 Impact Factor
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ABSTRACT: The generation of amyloid-beta peptide (Abeta) and its accumulation in amyloid plaques are generally recognized as key characteristics of Alzheimer's disease. A number of reports have indicated that Abeta can regulate the proliferation of neural precursor cells and adult neurogenesis, suggesting that this may underpin the cognitive decline and compromised olfaction also associated with the condition. Here we report that Abeta(1-42) treatment both in vitro and in vivo, as well as endogenous generation of Abeta in C100 and APP/PS1 transgenic models of Alzheimer's disease, stimulate neurogenesis of young adult subventricular zone precursors. The neurogenic effect of Abeta(1-42) was found to require expression of the p75 neurotrophin receptor (p75(NTR)) by the precursor cells, and activation of p75(NTR) by metalloprotease cleavage. However, precursors from 12-month-old APP/PS1 mice failed to respond to Abeta(1-42). Our results suggest that overstimulation of p75(NTR)-positive progenitors during early life might result in depletion of the stem cell pool and thus a more rapid decline in basal neurogenesis. This, in turn, could lead to impaired neurogenic function in later life.
Neurobiology of aging 04/2008; 30(12):1975-85. · 5.94 Impact Factor
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ABSTRACT: Beta-amyloid (Abeta) peptides may cause malfunction and death of neurons in Alzheimer's disease. We investigated the effect of Abeta on key transporters of amino acid neurotransmission in cells cultured from rat cerebral cortex. The cultures were treated with Abeta(25-35) at 3 and 10 microM for 12 and 24 h followed by quantitative analysis of immunofluorescence intensity. In mixed neuronal-glial cell cultures (from P1 rats), Abeta reduced the concentration of system A glutamine transporter 1 (SAT1), by up to 50% expressed relative to the neuronal marker microtubule-associated protein 2 (MAP2) in the same cell. No significant effects were detected on vesicular glutamate transporters VGLUT1 or VGLUT2 in neurons, or on glial system N glutamine transporter 1 (SN1). In neuronal cell cultures (from E18 rats), Abeta(25-35) did not reduce SAT1 immunoreactivity, suggesting that the observed effect depends on the presence of astroglia. The results indicate that Abeta may impair neuronal function and transmitter synthesis, and perhaps reduce excitotoxicity, through a reduction in neuronal glutamine uptake.
Neurochemical Research 03/2008; 33(2):248-56. · 2.24 Impact Factor
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ABSTRACT: It was previously observed that IL-1beta interferes with BDNF-induced TrkB-mediated signal transduction and protection of cortical neurons from apoptosis evoked by deprivation from trophic support [Tong L., Balazs R., Soiampornkul R., Thangnipon W., Cotman C.W., 2007. Interleukin-1beta impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol. Aging]. Here we investigated whether the effect of the cytokine on neurotrophin signaling is more general. The influence of IL-1beta on NT-3 signaling was therefore studied under conditions when NT-3 primarily activated the TrkC receptor. The cytokine reduced NT-3-induced activation of MAPK/ERK and Akt, but did not interfere with Trk receptor autophosphorylation. IL-1beta reduced tyrosine phosphorylation of the docking proteins, IRS-1 and Shc, which convey receptor activation to the downstream protein kinase cascades. These are the steps that are also inhibited by IL-1beta in BDNF-induced signal transduction. The functional consequences of the effect of IL-1beta on NT-3 signaling were severe, as NT-3 protection of the trophic support-deprived cortical neurons was abrogated. In view of the role in the maintenance and plasticity of neurons of ERK, Akt and CREB, which are activated by neurotrophins, elevated IL-1beta levels in the brain in Alzheimer's disease and other neurodegenerative diseases might contribute to the decline in cognitive functions before the pathological signs of the disease develop.
Brain Research 02/2008; 1188:189-97. · 2.73 Impact Factor
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ABSTRACT: Apolipoprotein E (APOE) gene on chromosome 19q13.2 is encoded by three common alleles designated as epsilon2, epsilon3 and epsilon4. In Alzheimer's disease (AD) the epsilon4 allele is over-represented and is considered to be a major genetic risk factor. Several methods have been developed to determine APOE genotypes. Among them, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) appears to be highly reliable. In this study, we improved the nonisotopic PCR-SSCP method for determining APOE genotypes in 42 cases of AD patients, 40 cases of non-AD dementia patients, and 49 cases of age-matched controls. DNA from the target sequence on APOE was amplified by PCR from peripheral blood genomic DNA. PCR products were electrophoresed in a non-denaturing polyacrylamide gel and visualized by silver staining. We found that the epsilon4 allele had a significantly high frequency of occurrence in AD patients (33.3%) compared with age-matched controls (13.3%) (chi(2) = 10.43, p = 0.001) and non-AD dementia (10%) (chi(2) = 13.02, p<0.001) whereas the epsilon3 allele was of high frequency in non-AD dementia (90%) compared with age-matched controls (85.7%) and AD patients (66.7%). APOE epsilon4 homozygotes were found only in AD groups. On the other hand, the epsilon2 allele was found only in an age-matched control. This study confirmed that the APOE psilon4 allele is a risk factor in Thai AD subjects and that the PCR-SSCP method is a rapid and useful means of detecting the APOE genotype in AD.
The Southeast Asian journal of tropical medicine and public health 07/2006; 37(4):793-7. · 0.60 Impact Factor
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ABSTRACT: The tumor suppressor gene locus is known to be partly responsible for the tumorigenesis of sporadic gliomas, but the genetic events that drive the neoplastic process of this tumor remain largely unknown. We correlated the results of loss of heterozygosity (LOH) analysis on chromosomes 10 and 17 and a point mutation analysis of a tumor suppressor gene, p53, in 21 patients with astrocytomas at different stages. LOH was determined in tumor and leukocyte DNAs of primary human central nervous system tumors. The incidence rate of brain tumors corresponded to every p53-coding exon for single-strand conformation polymorphisms (SSCP) and the mutations were confirmed by sequencing. p53 mutations were found in 2 of 10 glioblastomas (20%) and in 1 of 8 low-grade astrocytomas (12.5%). Similarly, LOH on chromosome 10 was also found in 2 of 10 glioblastomas (20%) and 1 of 8 low-grade astocytomas (12.5%). Neither of the p53 mutations nor LOH on chromosome 10 was observed together in the tumor types analyzed. Interestingly, the p53 mutations were found in 29% of patients with LOH on chromosome 17. The fact that p53 mutation and LOH on chromosome 17 were found together only in glioblastomas, suggested that these genetic changes may accumulate during astrocytoma progression.
Oncology Reports 02/2004; 11(1):207-11. · 1.84 Impact Factor
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ABSTRACT: It was previously observed that IL-1β interferes with BDNF-induced TrkB-mediated signal transduction and protection of cortical neurons from apoptosis evoked by deprivation from trophic support [Tong L., Balazs R., Soiampornkul R., Thangnipon W., Cotman C.W., 2007. Interleukin-1beta impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol. Aging]. Here we investigated whether the effect of the cytokine on neurotrophin signaling is more general. The influence of IL-1β on NT-3 signaling was therefore studied under conditions when NT-3 primarily activated the TrkC receptor. The cytokine reduced NT-3-induced activation of MAPK/ERK and Akt, but did not interfere with Trk receptor autophosphorylation. IL-1β reduced tyrosine phosphorylation of the docking proteins, IRS-1 and Shc, which convey receptor activation to the downstream protein kinase cascades. These are the steps that are also inhibited by IL-1β in BDNF-induced signal transduction. The functional consequences of the effect of IL-1β on NT-3 signaling were severe, as NT-3 protection of the trophic support-deprived cortical neurons was abrogated. In view of the role in the maintenance and plasticity of neurons of ERK, Akt and CREB, which are activated by neurotrophins, elevated IL-1β levels in the brain in Alzheimer's disease and other neurodegenerative diseases might contribute to the decline in cognitive functions before the pathological signs of the disease develop.
Brain Research.
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ABSTRACT: We present data on the effect of elevated concentrations of K+ ions (25 mM) and polylysine (PLL) coating of the substratum on the in vitro survival and behaviour of cells derived from 8-day-old rat cerebellum. The cells were grown in Eagle's basal medium in the presence of 10% foetal calf serum and cytosine arabinoside (10 μM), as a mitotic inhibitor. The most conspicuous effect of the high potassium was to facilitate the relatively long survival of the nerve cells, whereas PLL influenced the nerve cell attachment and thereby the size of the aggregates formed in the cultures. When cells were grown in high [K+] on PLL-coated dishes (standard conditions) over 70% of the plated cells survived beyond 7 DIV, and about 95% of the cells were small interneurones, tentatively identified as predominantly granule cells. The most numerous non-neuronal cells were glial fibrillary acid protein (GFA) positive astrocytes. The beneficial effect of high potassium on nerve cell survival was most prominent after 7 DIV, when it is known that transmission-associated neurochemical functions are just becoming detectable under the standard conditions. Initially (at 3 DIV) under all the tested conditions, and throughout the experimental period under the standard conditions, the dominant type of GFA-positive cells was the process bearing ‘differentiated’ astrocyte. When the conditions resulted in a great decrease in nerve cell numbers, on the other hand, flat astroblast-like cells became the most abundant cells in this class. Neurones grown on polylysine in the presence of 25 mM potassium extended neurites as early as 6 h after plating, and with longer culture times, an extensive network of fibres of neuronal origin was generated. Neurites did not seem to follow the processes of GFA-positive astrocytes in the cultures. Although there was a limited tendency for neuronal cell bodies to be positioned around astrocytes at 1 DIV, this became less marked with time, and no preferential association between astrocytes and neurones could be detected in the cultures later than 2 DIV.
Developmental Brain Research.
