It has been hypothesized that soluble forms of amyloid beta (Aß) and tau proteins in Alzheimer’s Disease (AD) interfere with neuronal activity causing memory deficits. Brain-derived neurotrophic factor (BDNF) is a protein regulating neuronal activity and is synthesized as a precursor pro-BDNF. BDNF regulates activity-dependent forms of synaptic plasticity such as long-term potentiation. Pro-BDNF downregulates synaptic activity and enhances long-term depression. Maturation of BDNF is regulated by tissue-type plasminogen activator (tPA) and by plasminogen activator inhibitor-1 (PAI-1). Thus, tPA/PAI-1 axis arbitrates the extracellular pro-BDNF/BDNF ratio. Plasma levels of PAI-1 are increased in AD patients. However, whether the process of BDNF maturation is altered in AD is not known. To verify this hypothesis, we will measure pro-BDNF/BDNF and tPA/PAI-1 ratios in serum and cerebrospinal fluid from AD patients and explore whether these changes correlate to those of neuropsychological and neuroimaging data. The outcome will be that of adding new biomarkers related to neuronal activity.

Předpokládá se, že rozpustné formy Amyloidu beta (Aß) a tau proteinu narušují neuronální aktivitu u Alzheimerovy nemoci (AN) a způsobují poruchy paměti. Brain-derived neurotrophic factor (BDNF) je protein regulující neuronální aktivitu a je syntetizován z prekurzoru pro-BDNF. BDNF posiluje synaptickou aktivitu mezi neurony a tím zvyšuje dlouhodobou potenciaci. Pro-BDNF naopak synaptickou aktivitu snižuje a zvyšuje tak dlouhodobou depresi mezi neurony. Maturace BDNF je regulována tkáňovým aktivátorem plazminogenu (tPA) a inhibitorem aktivátoru plazminogenu (tPA). Z toho vyplývá, že osa tPA/PAI-1 rozhoduje o extracelulárním poměru pro-BDNF/BDNF. U pacientů a AN byly pozorovány zvýšené hladiny PAI-1 v plasmě. Nicméně není známo, zda u pacientů s AN dochází k narušení procesu zrání BDNF. Tuto hypotézy budeme testovat pomocí měření poměru hladin pro-BDNF/BDNF a tPA/PAI-1 v krevním séru a mozkomíšním moku u pacientů s AN a budeme zjišťovat, zda tyto hladiny korelují s výsledky neuropsychologických testů a neurozobrazovacích metod. Výstupem projektu bude zavedení nových biomarkerů neuronové aktivity.

• Klíčová slova
• alzheimerova choroba, Alzheimer's disease, mírná kognitivní porucha, mild cognitive impairment, BDNF, Pro-BDNF, BDNF, pro-BDNF, PAI-1, tPA, PAI-1, tPA,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

Throughout development, neuronal progenitors undergo complex transformation into polarized nerve cells, warranting the directional flow of information in the neural grid. The majority of neuronal polarization studies have been carried out on rodent-derived precursor cells, programmed to develop into neurons. Unlike rodent neuronal cells, SH-SY5Y cells derived from human bone marrow present a sub-clone of neuroblastoma line, with their transformation into neuron-like cells showing a range of highly instructive neurobiological characteristics. We applied two-step retinoic acid (RA) and brain-derived neurotrophic factor (BDNF) protocol to monitor the conversion of undifferentiated SH-SY5Y into neuron-like cells with distinctly polarized axon-dendritic morphology and formation of bona fide synaptic connections. We show that BDNF is a key driver and regulator of the expression of axonal marker tau and dendritic microtubule-associated protein-2 (MAP2), with their sorting to distinct cellular compartments. Using selective kinase inhibitors downregulating BDNF-TrkB signaling, we demonstrate that constitutive activation of TrkB receptor is essential for the maintenance of established polarization morphology. Importantly, the proximity ligation assay applied in our preparation demonstrates that differentiating neuron-like cells develop elaborate synaptic connections enriched with hallmark pre- and postsynaptic proteins. Described herein findings highlight several fundamental processes related to neuronal polarization and synaptogenesis in human-derived cells, which are of major relevance to neurobiology and translational neuroscience.

• MeSH
• biologické markery MeSH
• buněčná diferenciace genetika   MeSH
• lidé MeSH
• mozkový neurotrofický faktor genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• neuroblastom genetika   metabolismus   patologie   MeSH
• neurogeneze genetika   MeSH
• neurony cytologie   metabolismus   MeSH
• reaktivní formy kyslíku MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIMS: To investigate the therapeutic potential of visual stimulation (VS) and BDNF in murine experimental autoimmune uveoretinitis (EAU). MAIN METHODS: Mice were immunized by subcutaneous injection of interphotoreceptor retinoid-binding protein in Freund's complete adjuvant and intravenous injection of pertussis toxin, and were then exposed to high-contrast VS 12 h/day (days 1-14 post-immunization). EAU severity was assessed by examining clinical score, visual acuity, inflammatory markers, and immune cells in the retina. The transcriptome of activated retinal cells was determined by RNA-seq using RNA immunoprecipitated in complex with phosphorylated ribosomal protein S6. The retinal levels of protein products of relevant upregulated genes were quantified. The effect of BDNF on EAU was tested in unstimulated mice by its daily topical ocular administration (days 8-14 post-immunization). KEY FINDINGS: VS attenuated EAU development and decreased the expression of pro-inflammatory cytokines/chemokines and numbers of immune cells in the retina (n = 10-20 eyes/group for each analysis). In activated retinal cells of control mice (n = 30 eyes/group), VS upregulated genes encoding immunomodulatory neuropeptides, of which BDNF and vasoactive intestinal peptide (VIP) also showed increased mRNA and protein levels in the retina of VS-treated EAU mice (n = 6-10 eyes/group for each analysis). In unstimulated EAU mice, BDNF treatment mimicked the protective effects of VS by modulating the inflammatory and stem cell properties of Müller cells (n = 5 eyes/group for each analysis). SIGNIFICANCE: VS effectively suppresses EAU, at least through enhancing retinal levels of anti-inflammatory and neuroprotective factors, VIP and BDNF. Our findings also suggest BDNF as a promising therapeutic agent for uveitis treatment.

• MeSH
• autoimunitní nemoci * imunologie   metabolismus   MeSH
• cytokiny metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• mozkový neurotrofický faktor * metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• retina metabolismus   účinky léků   MeSH
• retinitida * farmakoterapie   prevence a kontrola   imunologie   MeSH
• uveitida * metabolismus   farmakoterapie   imunologie   MeSH
• vazoaktivní intestinální peptid farmakologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Multiple sclerosis (MS) is the most common cause of nontraumatic neurological disability in Europe and North America. Growth factor expression could participate in the repair process of the demyelinating disease. Among growth factors, brain derived neurotrophic factors (BDNF) has been demonstrated to play an important role in neuronal and axonal survival. In the central nervous system (CNS ), neurons are the main source of BDNF. Another potential source are activated astrocytes, which are present in inflamed areas in the CNS as shown in MS. In this study, total protein concentration (TPC) and BDNF levels in the cerebrospinal fluid (CS F) samples from the patients with MS (n = 48) and control subjects (n = 53) were measured using a Bio-Rad protein assay and enzyme linked immunosorbent assay (ELISA). No significant change in the CS F TPC of patients with MS was seen as compared to normal CS F. The presence of BDNF in the CS F samples was shown by Western blot. Using ELISA , it was shown that the level of BDNF in the MS CS F is higher than in normal CS F. It is concluded that BDNF is a constant component of human CS F. Moreover, it could be implicated in the pathophysiology of MS.

• MeSH
• dospělí MeSH
• lidé MeSH
• mozkový neurotrofický faktor MeSH
• roztroušená skleróza MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH

Cíl: Stanovení alelové frekvence polymorfizmu p.Val66Met (rs6265) v genu pro mozkový neurotrofní faktor (brain-derived neurotrophic factor; BDNF) v české populaci. Přítomnost polymorfizmu p.Val66Met v genu BDNF je spojována s porušeným intracelulárním transportem a sekrecí BDNF. Změny v expresi a funkci BDNF jsou spojeny s různými onemocněními mozku a představují jeden z mechanizmů odpovědi na stres. Soubor a metodika: Retrospektivně bylo v kontrolní skupině vyšetřeno 317 vzorků DNA jedinců z české populace (173 mužů a 144 žen) ve věku 45–81 let. Polymorfizmus p.Val66Met v genu BDNF byl vyšetřen analýzou křivek tání. Výsledky: Frekvence mutantní alely (A) v kontrolní skupině činila 16,3 %; frekvence standardní alely (G) činila 83,7 %. Závěr: Byla stanovena frekvence polymorfizmu p.Val66Met v genu BDNF, která je srovnatelná s frekvencemi v okolních zemích.

Aim: To determine the allele frequency of the p.Val66Met (rs6265) polymorphism in BDNF gene (brain-derived neurotrophic factor, BDNF) in the Czech population. The p.Val66Met (rs6265) polymorphism in the BDNF gene is associated with impaired intracellular trafficking and secretion of BDNF. Alterations in BDNF expression and function are involved in different brain disorders and represent a major downstream mechanism for stress response. Material and methods: Retrospectively, 317 DNA control samples of Czech individuals aged between 45 and 81 years (173 men and 144 women), were examined for p.Val66Met polymorphism in the BDNF gene using the melting analysis. Results: Frequency of the mutant allele (A) was 16.3% and it was 83.7% for the wild type allele (G). Conclusion: The requency of the p.Val66Met polymorphism in the BDNF gene in the Czech population was determined.

• MeSH
• dospělí MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus * MeSH
• klinická studie jako téma MeSH
• lidé středního věku MeSH
• lidé MeSH
• mozkový neurotrofický faktor * genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Geografické názvy
• Česká republika MeSH

The aim of the study was to investigate the circulating levels of ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) in maternal serum and umbilical cord blood from respective pregnancies in pre-eclampsia (PE) cases and a control cohort. A total of 12 pre-eclampsia cases and 34 healthy controls were enrolled and the maternal peripheral blood - umbilical cord blood duos, were examined for BDNF and CNTF levels. BNDF levels were significantly higher in umbilical cord blood from pre-eclamptic pregnancies; there was also significant difference between maternal plasma and umbilical cord blood levels of BDNF (p < 0.001) in the controls. The CNTF levels in umbilical cord blood (CNTF-UCB) were significantly higher in PE cases than in the controls (p = 0.03). Significant differences were observed in expression of BDNF and CNTF proteins in maternal peripheral blood and umbilical cord blood between pre-eclampsia cases and healthy controls.

• MeSH
• biologické markery krev   MeSH
• ciliární neurotrofický faktor krev   MeSH
• dospělí MeSH
• fetální krev chemie   MeSH
• gestační stáří MeSH
• lidé MeSH
• mladý dospělý MeSH
• mozkový neurotrofický faktor krev   MeSH
• preeklampsie krev   MeSH
• studie případů a kontrol MeSH
• těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Brain-derived neurotrophic factor (BDNF) is a protein encoded, in humans, by BDNF gene on chromosome 11. BDNF protects adult neurons and promotes growth and differentiation during ontogenetic development but the nature and magnitude of its effects could be influenced by functional polymorphisms. The BDNF polymorphism Val66Met (rs6265) has been studied in the context of etiology of mental diseases including alcoholism. Alcoholism - a complex disorder known to be linked to several genes - has multiple manifestations, including sensory deficits such as those affecting vision. In the present study we examined a relationship between the Val66Met polymorphism, alcohol dependence and colour vision deficiency (CVD) in 167 alcohol-dependent men and 289 control male subjects. Statistical analysis revealed that almost half (about 48%) of the alcohol dependent men had a CVD. In addition we found that CVD was significantly associated (P=0.005) with the Val66Met polymorphism. The A allele containing 66Met promotes BDNF expression and this may protect humans against CVD induced by long-term excessive alcohol intake. The present findings indicate that alcohol-induced CVD does not depend solely on excessive alcohol consumption but is significantly influenced by genetic predisposition in the form of a specific BDNF polymorphism.

• MeSH
• alely MeSH
• alkoholismus komplikace   genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• mozkový neurotrofický faktor genetika   MeSH
• poruchy barevného vidění komplikace   genetika   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Alkoholismus způsobuje nejen poškození mozku, ale může způsobit také poruchy barvocitu. V naší asociační studii genetických dispozic k alkoholismu na 167 osobách závislých na alkoholu a 289 kontrolních jedincích jsme studovali vztah mezi kandidátními geny a alkoholismem. U osob zúčastněných ve studii jsme sledovali více faktorů, včetně poruchy barvocitu. Překvapivě jsme po statistické analýze zjistili, že 47,9 % alkoholiků trpí poruchou barvocitu a navíc že tato porucha barvocitu má souvislost s polymorfismem genu pro BDNF (brain-derived neurotrophic factor). Je dobře známo, že BDNF hraje úlohu v neurovývoji sítnice a v ochraně fotoreceptorů před apoptózou. Možná role genu pro BDNF na vzniku poruchy barvocitu u alkoholiků je diskutována.

Alcoholism induces the brain damage but it may also cause the color vision deficiency. In our association study of genetic dispositions to the alcoholism in 167 alcoholics and 289 non-alcoholic controls, we studied a relationship between candidate genes and alcoholism. In all subjects involved in this study many factors, e.g. color vision deficiencies, were examined. Surprisingly, after the statistical analysis, we found that 47.9% of alcoholics have problems with color vision deficiency and moreover that this color vision deficiency is in a relationship with the polymorphism of BDNF (Brain-derived neurotrophic factor) gene. It is well known that BDNF plays a role in the neurodevelopment of retina and in the protection of photoreceptors from apoptosis. Potential role of BDNF gene in the color vision deficiency in alcoholics is discussed.

• MeSH
• dospělí MeSH
• financování organizované MeSH
• interpretace statistických dat MeSH
• lidé MeSH
• mozkový neurotrofický faktor genetika   MeSH
• pití alkoholu škodlivé účinky   MeSH
• polymorfismus genetický genetika   MeSH
• poruchy barevného vidění diagnóza   etiologie   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH

BACKGROUND: Hypoxia effects on pulmonary artery structure and function are key to diseases such as pulmonary hypertension. Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF), can influence lung structure and function, and their role in the pulmonary artery warrants further investigation. In this study, we examined the effect of hypoxia on BDNF in humans, and the influence of hypoxia-enhanced BDNF expression and signaling in human pulmonary artery smooth muscle cells (PASMCs). METHODS AND RESULTS: 48h of 1% hypoxia enhanced BDNF and TrkB expression, as well as release of BDNF. In arteries of patients with pulmonary hypertension, BDNF expression and release was higher at baseline. In isolated PASMCs, hypoxia-induced BDNF increased intracellular Ca2+ responses to serotonin: an effect altered by HIF1α inhibition or by neutralization of extracellular BDNF via chimeric TrkB-Fc. Enhanced BDNF/TrkB signaling increased PASMC survival and proliferation, and decreased apoptosis following hypoxia. CONCLUSIONS: Enhanced expression and signaling of the BDNF-TrkB system in PASMCs is a potential mechanism by which hypoxia can promote changes in pulmonary artery structure and function. Accordingly, the BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and thus a potential target for therapy.

• MeSH
• arteria pulmonalis cytologie   MeSH
• hypoxie buňky účinky léků   MeSH
• lidé MeSH
• membránové glykoproteiny metabolismus   MeSH
• mozkový neurotrofický faktor metabolismus   MeSH
• myocyty hladké svaloviny cytologie   účinky léků   metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• regulace genové exprese účinky léků   MeSH
• tyrosinkinasy metabolismus   MeSH
• vápník metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

CONTEXT: Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. OBJECTIVE: To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. PATIENTS: 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. METHODS: SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). RESULTS: Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. CONCLUSIONS: Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations.

• MeSH
• energetický metabolismus fyziologie   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• mozkový neurotrofický faktor fyziologie   MeSH
• mutace * MeSH
• nádorové buněčné linie MeSH
• rodokmen MeSH
• steroidogenní faktor 1 genetika   MeSH
• steroidy biosyntéza   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH