116 results on '"Nikolac Perković, Matea"'
Search Results
2. PTSD, Immune System, and Inflammation
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Pivac, Nela, Vuic, Barbara, Sagud, Marina, Nedic Erjavec, Gordana, Nikolac Perkovic, Matea, Konjevod, Marcela, Tudor, Lucija, Svob Strac, Dubravka, Uzun, Suzana, Kozumplik, Oliver, Uzun, Sandra, Mimica, Ninoslav, Crusio, Wim E., Series Editor, Dong, Haidong, Series Editor, Radeke, Heinfried H., Series Editor, Rezaei, Nima, Series Editor, Steinlein, Ortrud, Series Editor, Xiao, Junjie, Series Editor, and Kim, Yong-Ku, editor
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- 2023
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3. Overview of metabolomic aspects in postpartum depression
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Konjevod, Marcela, Gredicak, Martin, Vuic, Barbara, Tudor, Lucija, Nikolac Perkovic, Matea, Milos, Tina, Svob Strac, Dubravka, Pivac, Nela, and Nedic Erjavec, Gordana
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- 2023
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4. Metabolic profiling of Alzheimer's disease: Untargeted metabolomics analysis of plasma samples
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Milos, Tina, Rojo, David, Nedic Erjavec, Gordana, Konjevod, Marcela, Tudor, Lucija, Vuic, Barbara, Svob Strac, Dubravka, Uzun, Suzana, Mimica, Ninoslav, Kozumplik, Oliver, Barbas, Coral, Zarkovic, Neven, Pivac, Nela, and Nikolac Perkovic, Matea
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- 2023
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5. Reduced plasma BDNF concentration and cognitive decline in veterans with PTSD
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Domitrovic Spudic, Sandra, Nikolac Perkovic, Matea, Uzun, Suzana, Nedic Erjavec, Gordana, Kozumplik, Oliver, Svob Strac, Dubravka, Mimica, Ninoslav, and Pivac, Nela
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- 2022
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6. Serotonin 5-HT2A receptor polymorphisms are associated with irritability and aggression in conduct disorder
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Nedic Erjavec, Gordana, Tudor, Lucija, Nikolac Perkovic, Matea, Podobnik, Josip, Dodig Curkovic, Katarina, Curkovic, Mario, Svob Strac, Dubravka, Cusek, Melita, Bortolato, Marco, and Pivac, Nela
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- 2022
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7. The association between BDNF C270T genetic variants and smoking in patients with mental disorders and in healthy controls
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Pivac, Nela, Nedic Erjavec, Gordana, Sagud, Marina, Nikolac Perkovic, Matea, Tudor, Lucija, Uzun, Suzana, Kovacic Petrovic, Zrnka, Konjevod, Marcela, Dvojkovic, Anja, Kozumplik, Oliver, Svob Strac, Dubravka, Peraica, Tina, Mimica, Ninoslav, Zivkovic, Maja, Hirasawa-Fujita, Mika, and Domino, Edward F.
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- 2022
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8. A Load to Find Clinically Useful Biomarkers for Depression
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Nikolac Perkovic, Matea, Sagud, Marina, Tudor, Lucija, Konjevod, Marcela, Svob Strac, Dubravka, Pivac, Nela, Crusio, Wim E., Series Editor, Dong, Haidong, Series Editor, Radeke, Heinfried H., Series Editor, Rezaei, Nima, Series Editor, Xiao, Junjie, Series Editor, and Kim, Yong-Ku, editor
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- 2021
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9. Alcohol-related phenotypes and platelet serotonin concentration
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Nedic Erjavec, Gordana, Bektic Hodzic, Jasminka, Repovecki, Senka, Nikolac Perkovic, Matea, Uzun, Suzana, Kozumplik, Oliver, Tudor, Lucija, Mimica, Ninoslav, Svob Strac, Dubravka, and Pivac, Nela
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- 2021
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10. Depression: Biological markers and treatment
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Nedic Erjavec, Gordana, Sagud, Marina, Nikolac Perkovic, Matea, Svob Strac, Dubravka, Konjevod, Marcela, Tudor, Lucija, Uzun, Sandra, and Pivac, Nela
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- 2021
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11. Effect of vortioxetine vs. escitalopram on plasma BDNF and platelet serotonin in depressed patients
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Dvojkovic, Anja, Nikolac Perkovic, Matea, Sagud, Marina, Nedic Erjavec, Gordana, Mihaljevic Peles, Alma, Svob Strac, Dubravka, Vuksan Cusa, Bjanka, Tudor, Lucija, Kusevic, Zorana, Konjevod, Marcela, Zivkovic, Maja, Jevtovic, Sasa, and Pivac, Nela
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- 2021
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12. Metabolomics analysis of microbiota-gut-brain axis in neurodegenerative and psychiatric diseases
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Konjevod, Marcela, Nikolac Perkovic, Matea, Sáiz, Jorge, Svob Strac, Dubravka, Barbas, Coral, and Rojo, David
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- 2021
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13. Genetic Markers of Alzheimer’s Disease
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Nikolac Perkovic, Matea, Pivac, Nela, LAMBRIS, JOHN D., Series Editor, CRUSIO, WIM E., Series Editor, REZAEI, NIMA, Series Editor, and Kim, Yong-Ku, editor
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- 2019
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14. Significant association of mu-opioid receptor 1 haplotype with tobacco smoking in healthy control subjects but not in patients with schizophrenia and alcohol dependence
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Konjevod, Marcela, Nikolac Perkovic, Matea, Svob Strac, Dubravka, Uzun, Suzana, Nedic Erjavec, Gordana, Kozumplik, Oliver, Tudor, Lucija, Mimica, Ninoslav, Hirasawa-Fujita, Mika, Domino, Edward F, and Pivac, Nela
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- 2020
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15. Metabolomic and glycomic findings in posttraumatic stress disorder
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Konjevod, Marcela, Tudor, Lucija, Svob Strac, Dubravka, Nedic Erjavec, Gordana, Barbas, Coral, Zarkovic, Neven, Nikolac Perkovic, Matea, Uzun, Suzana, Kozumplik, Oliver, Lauc, Gordan, and Pivac, Nela
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- 2019
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16. Cortisol in schizophrenia: No association with tobacco smoking, clinical symptoms or antipsychotic medication
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Nedic Erjavec, Gordana, Uzun, Suzana, Nikolac Perkovic, Matea, Kozumplik, Oliver, Svob Strac, Dubravka, Mimica, Ninoslav, Hirasawa-Fujita, Mika, Domino, Edward F., and Pivac, Nela
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- 2017
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17. No association between the serotonin transporter linked polymorphic region polymorphism and severity of posttraumatic stress disorder symptoms in combat veterans with or without comorbid depression
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Kovacic Petrovic, Zrnka, Nedic Erjavec, Gordana, Nikolac Perkovic, Matea, Peraica, Tina, and Pivac, Nela
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- 2016
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18. Monoamine oxidase and agitation in psychiatric patients
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Nikolac Perkovic, Matea, Svob Strac, Dubravka, Nedic Erjavec, Gordana, Uzun, Suzana, Podobnik, Josip, Kozumplik, Oliver, Vlatkovic, Suzana, and Pivac, Nela
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- 2016
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19. Biomarkers of aggression in dementia
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Gotovac, Kristina, Nikolac Perković, Matea, Pivac, Nela, and Borovečki, Fran
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- 2016
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20. Heavy Metals and Essential Metals Are Associated with Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease
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Babić Leko, Mirjana, primary, Mihelčić, Matej, additional, Jurasović, Jasna, additional, Nikolac Perković, Matea, additional, Španić, Ena, additional, Sekovanić, Ankica, additional, Orct, Tatjana, additional, Zubčić, Klara, additional, Langer Horvat, Lea, additional, Pleić, Nikolina, additional, Kiđemet-Piskač, Spomenka, additional, Vogrinc, Željka, additional, Pivac, Nela, additional, Diana, Andrea, additional, Borovečki, Fran, additional, Hof, Patrick R., additional, and Šimić, Goran, additional
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- 2022
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21. Serotonin Receptor Gene Polymorphisms Are Associated with Cerebrospinal Fluid, Genetic, and Neuropsychological Biomarkers of Alzheimer’s Disease
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Babić Leko, Mirjana, primary, Nikolac Perković, Matea, additional, Španić, Ena, additional, Švob Štrac, Dubravka, additional, Pleić, Nikolina, additional, Vogrinc, Željka, additional, Gunjača, Ivana, additional, Bežovan, Dora, additional, Nedić Erjavec, Gordana, additional, Klepac, Nataša, additional, Borovečki, Fran, additional, Zemunik, Tatijana, additional, Pivac, Nela, additional, Hof, Patrick R., additional, and Šimić, Goran, additional
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- 2022
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22. The association between the catechol-o-methyltransferase (COMT) genotypes with cognition in dementia
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Pivac, Nela, Nikolac Perković, Matea, Videtić Paska, Alja, Nedić Erjavec, Gordana, Uzun, Suzana, Kozumplik, Oliver, Borovečki, Fran, Filipčić, Igor, Mimica, Ninoslav, Babić Leko, Mirjana, Šimić, Goran, Švob Štrac, Dubravka, and Habek, Mario
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Alzheimer's disease ,catechol-o-methyl-transferase ,cognition ,dementia ,genetic variants - Abstract
Introduction: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are characterized by different phases of cognitive decline. In AD, there is a progressive impairment of acquired cognitive abilities while subjects with MCI show less severe cognitive disturbances. Cognitive dysfunction develops as a result of the complex interactions between multiple genetic, epigenetic, developmental, and environmental factors. Among many genes involved in cognition is the gene coding for catechol- O-methyltransferase (COMT), the enzyme responsible for the degradation of dopamine, resulting in the modulation of dopaminergic function. Therefore, COMT genetic variants were studied in various dementias characterized by cognitive loss. The aim of the study was to evaluate the possible association between COMT rs6269 and COMT rs4680 polymorphisms and cognitive decline in subjects with AD and MCI. Methods: Cognitive deterioration was assessed with the Mini-Mental State Examination (MMSE) and the Clock Drawing test (CDT) scores in 193 patients with AD and 269 subjects with MCI. COMT rs6269 and COMT rs4680 (Val158Met) were genotyped using the real-time PCR. Multiple linear regressions and Kruskal Wallis ANOVA were used to detect the association of the COMT rs6269 or COMT rs4680 genotypes with cognitive decline. Results: Multiple linear regression showed that COMT rs6269 was significantly associated with MMSE and CDT scores and these effects were affected by diagnosis and COMT rs6269 genotypes and age. In contrast, multiple linear regression revealed that COMT rs4680 was not significantly associated with MMSE or CDT scores, and the only significant effects were found for age and diagnosis. To further evaluate the effect of COMT polymorphisms on cognition, all subjects were subdivided into AA, GA, or GG genotype carriers of the COMT rs6269 or COMT rs4680, respectively, and according to MMSE or CDT scores. Carriers of the GG genotype of the COMT rs6269 had significantly (p=0.007) lower CDT scores than AA carriers, while other genotype groups did not differ significantly according to the CDT or MMSE scores. Conclusion: Although COMT rs4680 (Val158Met) was reported to be related to cognitive loss in various neuropsychiatric disorders, present results revealed a significant association between the other COMT polymorphism, rs6269, with cognitive deterioration in dementia.
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- 2023
23. Neuroinflammation, Gut-Brain Axis and Immunity in Neuropsychiatric Disorders
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Pivac, Nela, Vuić, Barbara, Šagud, Marina, Nedić Erjavec, Gordana, Nikolac Perković, Matea, Konjevod, Marcela, Tudor, Lucija, Švob Štrac, Dubravka, Uzun, Suzana, Kozumplik, Oliver, Uzun, Sandra, and Mimica, Ninoslav
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Brain-gut axis ,CRP ,Cardiovascular disease ,Chemokines ,Cytokines ,HPA axis ,Immune system ,Inflammation ,Kynurenine pathway ,Oxidative stress ,PTSD - Abstract
Posttraumatic stress disorder (PTSD) is a severe trauma and stress-related disorder associated with different somatic comorbidities, especially cardiovascular and metabolic disorders, and with chronic low-grade inflammation. Altered balance of the hypothalamic-pituitary-adrenal (HPA) axis, cytokines and chemokines, C-reactive protein, oxidative stress markers, kynurenine pathways, and gut microbiota might be involved in the alterations of certain brain regions regulating fear conditioning and memory processes, that are all altered in PTSD. In addition to the HPA axis, the gut microbiota maintains the balance and interaction of the immune, CNS, and endocrine pathways forming the gut-brain axis. Disbalance in the HPA axis, gut-brain axis, oxidative stress pathways and kynurenine pathways, altered immune signaling and disrupted homeostasis, as well as the association of the PTSD with the inflammation and disrupted cognition support the search for novel strategies for treatment of PTSD. Besides potential anti-inflammatory treatment, dietary interventions or the use of beneficial bacteria, such as probiotics, can potentially improve the composition and the function of the bacterial community in the gut. Therefore, bacterial supplements and controlled dietary changes, with exercise, might have beneficial effects on the psychological and cognitive functions in patients with PTSD. These new treatments should be aimed to attenuate inflammatory processes and consequently to reduce PTSD symptoms but also to improve cognition and reduce cardio-metabolic disorders associated so frequently with PTSD.
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- 2023
24. The potential protective role of dehydroepiandrosterone and its sulfate in the genetic and pharmacologically induced animal model of Alzheimer’s disease
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Vuić, Barbara, Miloš, Tina, Nikolac Perković, Matea, Nedić Erjavec, Gordana, Tudor, Lucija, Konjevod, Marcela, Švob Štrac, Dubravka, and Pavlek, Katarina
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Alzheimer´s disease ,DHEA ,DHEAS ,C57BL/6 ,3xTg-AD - Abstract
Alzheimer's disease (AD) is the most prevalent form of dementia, accounting for 60-70% of all dementia cases. It is a progressive and incurable neurodegenerative disorder characterized by the amyloid beta (Aβ) peptide deposition in the amyloid plaques and accumulation of hyperphosphorylated tau protein in the neurofibrillary tangles. It affects neuronal functioning and connectivity, resulting in a progressive loss of brain functions, with the cortex and hippocampus being primarily affected. The current AD therapy is only effective in alleviating the symptoms, whereas ongoing research aims at discovering new disease-modifying treatment strategies. The neurosteroids dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) have been studied for their neuroprotective potential in AD. Although these steroid hormones are abundant in the human blood, they are also produced de novo in neurons and glial cells, where their concentration is 6-8 times higher in comparison to periphery. In our research, we have utilized both genetic and pharmacologically induced mouse model of AD. The triple-transgenic AD (3xTg-AD) mouse is one of the most appropriate animal models of AD, displaying all main histopathological and behavioral features of AD, including age-dependent development of amyloid plaques, neurofibrillary tangles and progressive cognitive decline. The 3xTg-AD mice and C57BL/6 control mice were chronically treated with DHEAS using subcutaneously intrascapulary implanted osmotic pumps. The pharmacologically induced AD model was established by intracerebroventriculary injecting the C57BL/6 mice with Aβ oligomers and chronically administered with DHEA via intraperitoneal injection. Various cognitive and behavioral tests were performed on both models and analyzed using Noldus EthoVision XT software. Upon completion of the treatments and behavioral testing, the mice were euthanized and their brains were harvested for further analysis. Our results suggest that DHEA(S) could potentially serve as a protective agent against cognitive decline and other symptomatic presentations in mouse models of AD. Nevertheless, further validation of these results is necessary and it is imperative to extend our findings to include human blood samples to investigate potential therapeutic strategies of these neurosteroids in the future.
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- 2023
25. Association of gene polymorphisms encoding dopaminergic system components and platelet MAO-B activity with alcohol dependence and alcohol dependence-related phenotypes
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Nedic Erjavec, Gordana, Nenadic Sviglin, Korona, Nikolac Perkovic, Matea, Muck-Seler, Dorotea, Jovanovic, Tanja, and Pivac, Nela
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- 2014
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26. The association between galactosylation of immunoglobulin G and body mass index
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Nikolac Perkovic, Matea, Pucic Bakovic, Maja, Kristic, Jasminka, Novokmet, Mislav, Huffman, Jennifer E., Vitart, Veronique, Hayward, Caroline, Rudan, Igor, Wilson, James F., Campbell, Harry, Polasek, Ozren, Lauc, Gordan, and Pivac, Nela
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- 2014
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27. Brain-derived neurotrophic factor Val66Met polymorphism and alcohol-related phenotypes
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Nedic, Gordana, Nikolac Perkovic, Matea, Nenadic Sviglin, Korona, Muck-Seler, Dorotea, Borovecki, Fran, and Pivac, Nela
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- 2013
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28. Metabolomics in posttraumatic stress disorder: Untargeted metabolomic analysis of plasma samples from Croatian war veterans
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Konjevod, Marcela, Nedić Erjavec, Gordana, Nikolac Perković, Matea, Saiz, Jorge, Tudor, Lucija, Uzun, Suzana, Kozumplik, Oliver, Barbas, Coral, Švob Štrac, Dubravka, Žarković, Neven, and Pivac, Nela
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0301 basic medicine ,psychiatry ,metabolomics ,posttraumatic stress disorder ,Inflammation ,Bioinformatics ,medicine.disease_cause ,Affect (psychology) ,Biochemistry ,Gas Chromatography-Mass Spectrometry ,Mass Spectrometry ,Stress Disorders, Post-Traumatic ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Metabolomics ,Physiology (medical) ,Humans ,Medicine ,Veterans ,Psychiatry ,business.industry ,Neurotoxicity ,Posttraumatic stress disorder ,Basic Medical Sciences ,Omics ,medicine.disease ,030104 developmental biology ,BIOMEDICINE AND HEALTHCARE ,Etiology ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Oxidative stress ,Neuroscience - Abstract
Posttraumatic stress disorder (PTSD) is a severe, multifactorial and debilitating neuropsychiatric disorder, which can develop in a subset of individuals as a result of the exposure to severe stress or trauma. Such traumatic experiences have a major impact on molecular, biochemical and cellular systems, causing psychological and somatic alterations that affect the whole organism. Although the etiology of PTSD is still unclear, it seems to involve complex interaction between various biological genetic and environmental factors. Metabolomics, as one of the rapidly developing “omics” techniques, might be a useful tool for determining altered metabolic pathways and stress-related metabolites as new potential biomarkers of PTSD. The aim of our study was to identify metabolites whose altered levels allow us to differentiate between patients with PTSD and healthy control individuals. The study included two cohorts. The first, exploratory, group included 50 Croatian veterans with PTSD and 50 healthy control subjects, whereas a validation group consisted of 52 veterans with PTSD and 52 control subjects. The metabolomic analysis of plasma samples was conducted using liquid chromatography coupled with mass spectrometry (LC- MS), as well as gas chromatography coupled with mass spectrometry (GC-MS). The LC-MS analysis determined significantly different levels of two glycerophospholipids, PE(18:1/0:0) and PC(18:1/0:0), between control subjects and PTSD patients in both cohorts. The altered metabolites might play a role in multiple cellular processes, including inflammation, mitochondrial dysfunction, membrane breakdown, oxidative stress and neurotoxicity, which could be associated with PTSD pathogenesis.
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- 2021
29. Three different methods confirmed the association of macro and microelements with cerebrospinal fluid biomarkers of Alzheimer's disease
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Mihelčić, Matej, Babić Leko, Mirjana, Jurasović, Jasna, Nikolac Perković, Matea, Španić, Ena, Sekovanić, Ankica, Orct, Tatjana, Zubčić, Klara, Langer Horvat, Lea, Pleić, Nikolina, Kiđemet-Piskač, Spomenka, Vogrinc, Željka, Pivac, Nela, Borovečki, Fran, Hof, Patrick R., Šimić, Goran, and Sebu, Cristiana
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Alzheimer's disease ,cerebrospinal fluid protein biomarkers ,cognitive impairment ,inductively coupled plasma mass spectroscopy ,machine learning ,metalloids ,metals ,plasma ,principal component analysis ,redescription mining ,trace elements - Abstract
The homeostasis of metals is altered in the brain of Alzheimer’s disease (AD) patients. It was proposed that changes in metal homeostasis are related to AD pathology. Additionally, metals that are not present in the brain under normal circumstances (such as mercury, lead and cadmium) were associated with AD pathogenesis. The aim of this study was to test if macro and microelements (Li, B, Na, Mg, Al, S, K, Ca, Cr, Fe, Co, Mn, Ni, Cu, Zn, As, Se, Sr, Mo, Cd, Ba, Tl, Pb, and Hg) measured in cerebrospinal fluid (CSF) and plasma of patients with dementia are associated with CSF biomarkers of AD. CSF AD biomarkers reflect pathological changes in AD brain, while the involvement of different metals in AD pathogenesis is still the matter of debate. Macro and microelements were determined by inductively coupled plasma mass spectroscopy (ICP-MS), while CSF biomarkers were measured by enzyme-linked immunosorbent assays (ELISA). Macro and microelements were measured in CSF of 194 subjects and in plasma of 144 subjects (study included overall 125 AD patients, 50 patients with mild cognitive disorder and 19 healthy controls). We used three different statistical methods to test the association of macro and microelements with CSF biomarkers of AD. All three methods (simple correlation and two machine learning algorithms ; redescription mining and principal component analysis [PCA]) demonstrated the association of macro and microelements with CSF biomarkers of AD. Possible explanations for association of macro and microelements with CSF biomarkers of AD await elucidation of their environmental sources or detection of their release from brain tissue due to cell death. Also, these results should be further validated on larger cohorts.
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- 2022
30. Neuroprotective actions of DHEA and DHEAS in primary mouse neurons and SH-SY5Y cells exposed to toxic amyloid beta oligomers
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Vuić, Barbara, Miloš, Tina, Nikolac Perković, Matea, Nedić Erjavec, Gordana, Tudor, Lucija, Konjevod, Marcela, Pivac, Nela, Švob Štrac, Dubravka (Ruder Boskovic Institute, Zagreb, Croatia), Mršić-Pelčić, Jasenka, Vitezić, Dinko, and Janković, Tamara
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DHEA ,DHEAS ,BDNF ,Alzheimer´s disease ,amyloid beta aggregation - Abstract
Introduction: Alzheimer´s disease (AD) is neurodegenerative disease characterized by cognitive impairment and progressive synaptic damage accompanied by neuronal loss. The causes of amyloid beta aggregation that form amyloid plaques in the pathogenesis of AD has been debated for more than 25 years and it is supposed that amyloid beta oligomers may be the toxic factors acting on a very early stage of AD. Currently available therapy provides only symptomatic treatment, while many studies of new effective drugs have so far been unsuccessful. Therefore, neurosteroids dehydroepiandrosterone (DHEA) and its sulfated form dehydroepiandrosterone sulfate (DHEAS) are of a great interest due to their potential to modulate neurogenesis, neuronal growth and differentiation, as well as neuroprotection. Materials and methods: Neuroprotective effects of DHEA and DHEAS were investigated using primary mouse neurons, isolated from C57BL/6 mice embryos, and human SH-SY5Y neuroblastoma cells simultaneously exposed to toxic amyloid beta oligomers during 24 hours. Various assays (MTT, Muse, Promega) were used to determine cell viability and underlying mechanisms, while GraphPad Prism was used to interpret the obtained results. Results: Our results demonstrated that DHEA and DHEAS exert neuroprotective actions on primary mouse neurons and SH-SY5Y cells exposed to amyloid beta oligomers, probably via anti-apoptotic mechanisms. Conclusions: These findings suggest that DHEA and DHEAS may have therapeutic effects against amyloid beta toxicity. DHEA(S) could potentially represent novel preventive and/or therapeutic agents for AD in the future. This study needs to be confirmed and extended by further in vitro research and studies using animal models and human samples.
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- 2022
31. Neuroprotective effects of DHEA(S) and BDNF in an in vitro model of Parkinson's disease
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Miloš, Tina, Švob Štrac Dubravka, Nikolac Perković Matea, Tudor Lucija, Nedić Erjavec Gordana, Vuić Barbara, Konjevod Marcela, and Pivac Nela
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Parkinson diseases ,DHEA ,DHEAS ,BDNF - Abstract
Parkinson’s disease (PD) is a neurodegenerative disease characterized by a selective loss of dopaminergic (DA) neurons and accumulation of α- synuclein in the substantia nigra. It is considered that gene mutations, environmental factors and aging are causative factors of PD. Understanding the mechanisms involved in neurodegeneration is the key to identifying potential therapeutic strategies for PD. Neurotoxins, such as rotenone and 6- hydroxidopamine are widely used to induce in vivo and in vitro model of PD. These neurotoxins induce mitochondrial dysfunction and increase oxidative stress, which leads to neuronal degeneration and cell death by apoptosis. Neurosteroids, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), are the most abundant steroid hormones and can be synthesized de novo in the brain. Levels of DHEA(S) decrease with age and play an important role in brain aging and neurodegeneration. Neurotrophin, brain-derived neurotrophic factor (BDNF) is also involved in neuroprotection and neuroregeneration, while decreased levels of BDNF were observed in the aging process and in neurodegenerative diseases such as PD. In this study we have investigated potential neuroprotective effects of DHEA(S) and BDNF in four different cell models: primary mouse neurons, SH-SY5Y neuroblastoma cells, PC12 and N27 cells. These cells were injured with rotenone or 6-hydroxidopamine to induce an in vitro model of PD. In addition, cells were treated with DHEA(S) and BDNF separately and combined to investigate their interactions and neuroprotective potential. The obtained results suggest that DHEA(S) and BDNF may play important role in prevention and treatment of PD.
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- 2022
32. Potential therapeutic interventions targeting amyloid beta toxicity (in vitro model of Alzheimer ´s disease)
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Vuić, Barbara, Nikolac Perković, Matea, Nedić Erjavec, Gordana, Tudor, Lucija, Konjevod, Marcela, Miloš, Tina, Švob Štrac, Dubravka, and Schneider, Petra
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Alzheimer´s disease ,amyloid beta oligomers ,DHEA ,DHEAS ,BDNF - Abstract
Alzheimer´s disease (AD) is a progressive neurodegenerative disorder that accounts for about 70% of all dementia cases. The AD pathogenesis is characterized by the aggregation of amyloid β (Aβ) peptides into extracellular senile plaques, and the formation of intracellular neurofibrillary tangles by the hyperphosphorylated tau protein. Although both structures are considered to cause a significant loss of neurons and synapses, the Aβ hypothesis has been the dominant opinion for more than 25 years [1]. The intraneuronal accumulation of Aβ peptides may precede the generation of Aβ plaques and neurofibrillary tangles formation. The Aβ peptides are known to self-assemble into dimer, trimer and higher-order oligomers, which are believed to be the main source of toxicity by causing the death of neurons [2]. Since current therapy (cholinesterase inhibitors donepezil, galantamine and rivastigmine, as well as memantine, an N-methyl D-aspartate receptor antagonist) is still symptomatic, potential disease-modifying treatment strategies have been extensively investigated [3]. In addition to positive effects on overall human health, neurosteroids dehydroepiandrosterone (DHEA) and its sulfated form dehydrepiandrosterone sulfate (DHEAS) [4], as well as neurotrophin brain-derived neurotrophic factor (BDNF) [5], are of a great interest as potential therapeutic targets for AD, due to their involvement in neurogenesis, synaptic plasticity, neuronal growth, differentiation, protection, and survival. In our laboratory, cultured primary neurons derived from C57BL/6 mice were exposed to various Aβ preparations to optimize the in vitro model of AD. To investigate the potential neuroprotective actions against Aβ toxicity, primary neuronal cultures were treated with DHEA/S, BDNF and their combination and their effects on the cell viability and mechanisms of action were studied using various cell-based and biochemical assays. Our results suggesting neuroprotective effects of DHEA/S, BDNF and their combination could point to the new therapeutic interventions for this still incurable disease. However, our findings should be confirmed by further in vitro research, as well as by in vivo experiments using AD animal models and human blood samples.
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- 2022
33. Epigenetic, genetic, and expression analysis of brain-derived neurotrophic factor in Alzheimer's disease
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Tudor, Lucija, Nikolac Perković, Matea, Babić Leko, Mirjana, Videtič Paska, Alja, Kouter, Katarina, Miloš, Tina, Nedić Erjavec, Gordana, Vuić, Barbara, Konjevod, Marcela, Šimić, Goran, Borovečki, Fran, Pivac, Nela, Mršić-Pelčić, Jasenka, Vitezić, Dinko, and Janković, Tamara
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Alzheimer's disease ,amyloid-beta1-42 ,brain-derived neurotrophic factor (BDNF) ,BDNF gene polymorphisms ,cerebrospinal fluid ,methylation status ,next generation sequencing ,plasma ,quantitative PCR - Abstract
Introduction The most common dementia type is Alzheimer's disease (AD), characterized by progressive cognitive decline and neuronal death, which is often attributed to the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles in the brain. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in neurogenesis and neuroplasticity. Therefore, our aim was to investigate the BDNF alternations in AD, at the genetic, epigenetic, and expression levels. Materials and methods The study included 254 patients with AD and mild cognitive impairment (MCI), as a comparative group. Plasma BDNF and cerebrospinal fluid (CSF) Aβ1–42 protein levels were measured with enzyme-linked immunosorbent assay. Quantitative PCR was used to determine the five BDNF gene polymorphisms and BDNF mRNA expression in peripheral white blood cells. The next-generation sequencing was used to determine the methylation status of nine amplicons covering 169 CpG sites in the BDNF gene region. The data were analyzed using GraphPad Prism v4.00 software. Results The results demonstrated increased BDNF plasma concentration in AD patients compared to MCI group, and its positive correlation with Aβ1–42 CSF levels. Tested BDNF polymorphisms were not associated with AD ; however, lower methylation levels, especially in BDNF3 and BDNF9 amplicon region and lower expression of the BDNF gene in peripheral blood were detected in AD patients, compared to MCI subjects. Conclusions These findings could help to elucidate the complex role of BDNF in AD, as well as its potential as an easily accessible peripheral biomarker and novel therapeutic strategy for AD.
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- 2022
34. Plasma brain-derived neurotrophic factor (BDNF) concentration as a predictor of cognitive decline
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Pivac, Nela, Domitrović Spudić, Sandra, Nikolac Perković, Matea, Uzun, Suzana, Nedić Erjavec, Gordana, Kozumplik, Oliver, Švob Štrac, D, Mimica, Ninoslav, Šimić, Goran, and Mimica, Ninoslav
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Alzheimer’s disease ,brain-derived neurotrophic factor ,cognition ,mild cognitive impairment ,post-traumatic stress disorder - Abstract
Aims: Brain-derived neurotrophic factor (BDNF) regulates neuronal survival, neurogenesis, synaptic plasticity and cognition. Changes in BDNF signaling and altered concentration of mature BDNF protein were associated with cognitive decline in various disorders related to older age and neuropsychiatric disorders, such as mild cognitive impairment (MCI) and Alzheimer’s disease (AD), but also with stress and trauma related disorder, such as post-traumatic stress disorder (PTSD). There are inconsistent data on the association between blood BDNF levels and cognitive decline in different patient’s groups. This study aimed to evaluate cognitive decline and plasma BDNF concentration in male subjects: patients with AD, subjects with MCI, and veterans with combat- related PTSD, and to compare these data in healthy controls, in order to verify if plasma BDNF concentration might be used as an easy obtainable peripheral marker of cognitive worsening in AD, MCI and PTSD. Methods: Diagnoses were made using SCID based on DSM-5 criteria, and NINCDS-ADRDA criteria. Cognitive decline was assessed using the MMSE and Clock Drawing test (CDT). Plasma BDNF concentration was determined using the commercial enzyme-linked immunosorbent assay. Results: Plasma BDNF concentration was significantly decreased in patients with MCI or AD and in veterans with PTSD compared to values in healthy control subjects. Cognitive performances, evaluated using the MMSE and CDT scores, were significantly reduced in patients with MCI or AD and in veterans with PTSD compared to scores in healthy control subjects. Subjects with MCI and veterans with PTSD had comparable, reduced plasma BDNF concentration and decreased MMSE and CDT scores that were significantly different from the values in healthy control subjects. Conclusion: The results of this study confirmed that plasma BDNF concentration was reduced in different groups of cognitively impaired subjects, such as those with MCI, AD and PTSD, and might be used as a biomarker of cognitive worsening in these participants. These data also advise that veterans with PTSD should be further evaluated with additional cognitive tests of with to be able to early detect and predict cognitive dysfunction. Strategies that might help restore blood BDNF levels and improve cognitive functions are recommended for cognitively impaired participants.
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- 2022
35. The association of serotonin receptor genes polymorphisms with CSF, genetic, and neuropsychological biomarkers of Alzheimer's disease
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Babić Leko, Mirjana, Nikolac Perković, Matea, Švob Štrac, Dubravka, Pleić, Nikolina, Gunjača, Ivana, Klepac, Nataša, Borovečki, Fran, Pivac, Nela, Zemunik, Tatijana, Hof, Patrick R., Šimić, Goran, Šimić, Goran, and Mimica, Ninoslav
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Alzheimer's disease ,serotonin receptors ,biomarkers ,genetics ,cerebrospinal fluid - Abstract
Serotonergic receptors are affected in Alzheimer's disease (AD). The overall decrease in the serotonergic transmission is also observed in AD. Previous studies showed the association of polymorphisms in genes for serotonin (5HT) receptors with behavioral and psychological symptoms of dementia (BPSD). In this study, we aimed to test if individuals carrying different genotypes in 5HTR2A rs 6313 (T102C), 5HTR1B rs13212041, 5HTR6 rs1805054 (C267T), and 5HTR2C rs 3813929 (-795C/T) polymorphisms have a higher risk for development of AD. Cerebrospinal fluid (CSF) AD biomarkers, neuropsychological tests, and apolipoprotein E (APOE) haplotype were determined in 115 AD patients and 53 mildly cognitively impaired patients, while 2701 cognitively healthy individuals with determined APOE haplotype were also included. We observed that all four analyzed polymorphisms in genes for 5HT receptors showed an association with either CSF, neuropsychological or genetic biomarkers of AD. Thus, the potential of these polymorphisms as early genetic biomarkers of AD should be further investigated.
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- 2022
36. Polymorphisms within serotonin receptor genes are associated with genetic, cerebrospinal fluid and neuropsychological biomarkers of Alzheimer’s disease
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Babić Leko, Mirjana, Nikolac Perković, Matea, Španić, Ena, Švob Štrac, Dubravka, Pleić, Nikolina, Vogrinc, Željka, Gunjača, Ivana, Klepac, Nataša, Borovečki, Fran, Pivac, Nela, Zemunik, Tatijana, Hof, Patrick R., Šimić, Goran, and Sebu, Cristiana
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Alzheimer's disease ,APOE genotype ,behavioral and psychological symptoms of dementia ,cerebrospinal fluid biomarkers ,cognitive impairment ,neuropsychological testing ,polymorphisms ,receptors ,serotonin - Abstract
Decrease in serotonergic transmission throughout the brain is among the earliest pathological changes in Alzheimer’s disease (AD). Serotonergic receptors are also affected in AD. Polymorphisms in genes for serotonin (5HT) receptors were mostly associated with behavioral and psychological symptoms of dementia (BPSD). In this study we aimed to test if individuals carrying different genotypes in 5HTR1B rs13212041, 5HTR2A rs6313 (T102C), 5HTR2C rs3813929 (-795C/T) and 5HTR6 rs1805054 (C267T) polymorphisms have higher risk for development of AD. Study included 115 AD patients and 53 mild cognitive impairment patients with determined cerebrospinal fluid (CSF) AD biomarkers, neuropsychological tests, and apolipoprotein E (APOE) haplotype and 2701 cognitively healthy individuals with determined APOE haplotype. All four analysed polymorphisms of serotonin receptor genes showed the association with either genetic, CSF or neuropsychological biomarkers of AD. Thus, these polymorphisms deserve further investigation as potential genetic biomarkers and therapeutic targets for AD.
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- 2022
37. THE PROTECTIVE ACTIONS OF DHEA/S AND BDNF AGAINST OXIDATIVE STRESS IN AN IN VITRO MODEL OF VASCULAR DEMENTIA
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Vuić, Barbara, Nikolac Perković, Matea, Nedić Erjavec, Gordana, Tudor, Lucija, Miloš, Tina, Pivac, Nela, Konjevod, Marcela, and Švob Štrac, Dubravka
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vascular dementia, oxidative stress, DHEA, DHEAS, BDNF - Abstract
Vascular dementia (VaD), the second most common form of dementia, is generally underrecognized and still poorly understood disease. It develops when the brain´s blood supply is blocked or reduced, causing deprivation of oxygen and nutrients and resulting in damage and death of neurons. The brain is highly susceptible to oxidative stress, due to its richness in fatty acids sensitive to peroxidation, as well as due to high oxygen consumption and free radicals accumulation. Oxidative stress in VaD, characterized by the exacerbated production of reactive oxygen species and insufficient antioxidant defense system, increases neuronal cell abnormalities and triggers apoptosis, leading to cognitive dysfunction and dementia. Neurosteroids dehydroepiandrosterone and dehydroepiandrosterone sulfate (DHEA/S) and neurotrophin brain-derived neurotrophic factor (BDNF) have attracted the attention of researchers investigating their involvement in various brain functions such as neural survival, plasticity, cognition and behavior. The aim of this study was to investigate the protective potential of DHEA/S and BDNF in promoting neuronal survival and preventing oxidative stress caused by brain ischemia, a common characteristic of VaD. Oxygen-glucose deprivation (OGD) was performed in primary mouse neurons derived from C57BL/6 mice, and human SH-SY5Y neuroblastoma cells as in vitro model of VaD. The cells were cultured in glucose- and serum-free medium in a modular incubator chamber filled with N2. Before or after OGD, cells were treated with DHEA/S and BDNF and cell viability and oxidative stress parameters were determined. Our results suggested protective effects of DHEA/S and BDNF against oxidative damage induced by the ischemic injury in neuronal cells.
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- 2022
38. Heavy Metals and Essential Metals Are Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease.
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Babić Leko, Mirjana, Mihelčić, Matej, Jurasović, Jasna, Nikolac Perković, Matea, Španić, Ena, Sekovanić, Ankica, Orct, Tatjana, Zubčić, Klara, Langer Horvat, Lea, Pleić, Nikolina, Kiđemet-Piskač, Spomenka, Vogrinc, Željka, Pivac, Nela, Diana, Andrea, Borovečki, Fran, Hof, Patrick R., and Šimić, Goran
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HEAVY metals ,ALZHEIMER'S disease ,CEREBROSPINAL fluid ,POLLUTANTS ,METALS ,MACHINE learning - Abstract
Various metals have been associated with the pathogenesis of Alzheimer's disease (AD), principally heavy metals that are environmental pollutants (such as As, Cd, Hg, and Pb) and essential metals whose homeostasis is disturbed in AD (such as Cu, Fe, and Zn). Although there is evidence of the involvement of these metals in AD, further research is needed on their mechanisms of toxicity. To further assess the involvement of heavy and essential metals in AD pathogenesis, we compared cerebrospinal fluid (CSF) AD biomarkers to macro- and microelements measured in CSF and plasma. We tested if macro- and microelements' concentrations (heavy metals (As, Cd, Hg, Ni, Pb, and Tl), essential metals (Na, Mg, K, Ca, Fe, Co, Mn, Cu, Zn, and Mo), essential non-metals (B, P, S, and Se), and other non-essential metals (Al, Ba, Li, and Sr)) are associated with CSF AD biomarkers that reflect pathological changes in the AD brain (amyloid β
1–42 , total tau, phosphorylated tau isoforms, NFL, S100B, VILIP-1, YKL-40, PAPP-A, and albumin). We used inductively coupled plasma mass spectroscopy (ICP-MS) to determine macro- and microelements in CSF and plasma, and enzyme-linked immunosorbent assays (ELISA) to determine protein biomarkers of AD in CSF. This study included 193 participants (124 with AD, 50 with mild cognitive impairment, and 19 healthy controls). Simple correlation, as well as machine learning algorithms (redescription mining and principal component analysis (PCA)), demonstrated that levels of heavy metals (As, Cd, Hg, Ni, Pb, and Tl), essential metals (Ca, Co, Cu, Fe, Mg, Mn, Mo, Na, K, and Zn), and essential non-metals (P, S, and Se) are positively associated with CSF phosphorylated tau isoforms, VILIP-1, S100B, NFL, and YKL-40 in AD. [ABSTRACT FROM AUTHOR]- Published
- 2023
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39. The Association of Essential Metals with APOE Genotype in Alzheimer’s Disease
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Babić Leko, Mirjana, primary, Jurasović, Jasna, additional, Nikolac Perković, Matea, additional, Španić, Ena, additional, Sekovanić, Ankica, additional, Orct, Tatjana, additional, Lukinović Škudar, Vesna, additional, Bačić Baronica, Koraljka, additional, Kiđemet-Piskač, Spomenka, additional, Vogrinc, Željka, additional, Pivac, Nela, additional, Borovečki, Fran, additional, Hof, Patrick R., additional, and Šimić, Goran, additional
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- 2021
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40. Therapeutic potential of neurosteroids and neurotrophins in dementia
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Vuić, Barbara, Švob Štrac, Dubravka, Nedić Erjavec, Gordana, Nikolac Perković, Matea, Tudor, Lucija, Konjevod, Marcela, Pivac, Nela, Erhardt, Julija, and Barišić, Dajana
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dementia ,Alzheimer´s disease ,DHEA ,DHEAS ,BDNF - Abstract
Dementia is a syndrome of progressive cognitive decline that usually affects older people. It will become one of the leading global problems in the future due to accelerated aging of the population and increase of life expectancy. Alzheimer´s disease (AD) is the most common progressive and incurable neurodegenerative disease. Neuroimaging techniques have shown a decrease in brain volume and weight in AD patients, as well as dilation of lateral brain chambers, while post-mortem studies have found extracellular accumulations of amyloid beta (Aβ) in senile plaques and intracellular neurofibrillary tangles as a result of accumulating hyperphosphorylated tau protein. Current available therapy is based on symptomatic treatment or alleviation of disease symptoms and numerous studies of new effective drugs have failed. Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), the most abundant steroids in human blood whose concentrations decrease significantly with aging, are involved in brain functions such as neural plasticity, learning, memory and behavior and have anti-inflammatory, antioxidant and anti-glucocorticoid effects. Brainderived neurotrophic factor (BDNF) is one of trophic factors that is involved in various aspects of neuronal development and differentiation, as well as plasticity and repair mechanisms. BDNF promotes the survival and differentiation of neurons that are damaged in AD. The purpose of this study is to investigate the neuroprotective potential and mechanisms of action of DHEA(S) and BDNF in dementia, through a combination of cellular, animal and human experiments. Currently, we are conducting in vitro experiments in which we study the protective effects of DHEA(S) and BDNF on isolated primary neurons from C57BL/6 mouse strain, treated with toxic Aβ-oligomers.
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- 2021
41. Genske varijante moždanog neurotrofnog čimbenika moduliraju biomarkere iz cerebrospinalne tekućine u ispitanika s Alzheimerovom bolesti
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Pivac, Nela, Nikolac Perković, Matea, Babić Leko, Mirjana, Borovečki, Fran, Švob Štrac, Dubravka, Nedić Erjavec, Gordana, Mimica, Ninoslav, and Šimić, Goran
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Alzheimerova bolest ,moždani neurotrofni čimbenik ,genske varijante ,biološki biljezi u cerebrospinalnoj tekućini - Abstract
Sporadični oblik Alzheimerove bolesti (AD) s kasnim početkom je najčešći uzrok demencije. Mnogobrojni rizični čimbenici za AD su starija dob, različiti čimbenici iz okoline i genetski čimbenici. Ti su rizični čimbenici iz okoline odgovorni za raniji početak bolesti, bržu progresiju, jaču težinu simptoma. Uz mnoštvo rizičnih gena, gen za moždanih neurotrofni čimbenik BDNF kodira protein BDNF koji je uključen u modulaciju plastičnosti mozga, rast neurona, preživljavanje, funkciju, neurogenezu, regeneraciju, ali i apoptozu. BDNF ima ulogu i u promjenama moždanih puteva jer njegove promjene utječu na fiziologiju i neuroplastičnost. Snižene koncentracije središnjeg i perifernog BDNF-a povezane su s različitim neurodegenerativnim i psihijatrijskim poremećajima, uključujući i AD. Genske varijante BDNF-a mogu objasniti interindividualne razlike koje se javljaju u AD-u. Budući da nema izlječenja AD-a, validirani, specifični i selektivni biomarkeri povezani s endofenotipovima koji se javljaju unutar kliničke slike AD-a potrebni su, ali još uvijek nedostupni. Studija je ciljala istražiti povezanost različitih BDNF polimorfizama (rs6265, rs11030104, rs7934165, rs1519480, rs56164415) s koncentracijom biomarkera iz cerebrospinalne tekućine (CSF): amiloida beta (1-42), ukupnih tau proteina, fosforiliranih tau proteina (p-tau181, p-tau199, p- tau231) i proteina nalik vizininu (VILIP-1) u bolesnika s AD s kasnim početkom. Mogući AD (N=114) je dijagnosticiran temeljem DSM-IV i NINDS-ADRDA kriterija. Pronađena je značajna povezanost između BDNF rs11030104, rs11030104 i rs7934165 i CSF biomarkera, dok drugi polimorfizmi nisu bili povezani s CSF biomarkerima. Naime, BDNF rs6265 bio je značajno povezan s koncentracijom p-tau181, jer su nositelji A alela prema nositeljima GG imali značajno sniženu koncentraciju p-tau181. Značajna je povezanost utvrđena između BDNF rs11030104 i koncentracije p-tau181 i p-tau199, jer su nositelji GG genotipa imali značajno nižu koncentraciju p- tau181 i p-tau199 naspram nositelja AA ili AG genotipova. Uz to je pronađen tren prema odnosu između BDNF rs7934165 i koncentracije VILIP-1, budući da su nositelji AA imali nižu VILIP-1 koncentraciju prema nositeljima G alela. Naši podatci trebaju potvrdu na većim skupinama ispitanika, no ti preliminarni podatci upućuju na povezanost između BDNF genskih varijanti (rs11030104, rs11030104 i rs7934165) i CSF biomarkera koji su inače povišeni u AD, fosforiliranih tau (p-tau181 i p-tau199), te VILIP-1 proteina u bolesnika s kasnim početkom AD.
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- 2021
42. DHEA, DHEAS, BDNF and their synergistic action as a potential therapy for Alzheimer´s disease
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Vuić, Barbara, Nikolac Perković, Matea, Nedić Erjavec, Gordana, Tudor, Lucija, Konjevod, Marcela, Pivac, Nela, and Švob Štrac, Dubravka
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Alzheimer´s disease ,DHEA ,DHEAS ,BDNF ,primary mouse neurons ,synergistic action - Abstract
Alzheimer´s disease (AD), the most common type of dementia, is still without effective treatment. This neurodegenerative disease is characterized by progressive cognitive decline, neuronal death, as well as accumulation of amyloid beta (Aβ) senile plaques and tau neurofibrillary tangles in the brain. Neurosteroids dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), potent modulators of neurogenesis, neuronal growth, differentiation and neuroprotection, decrease with age and play an important role in brain aging and neurodegeneration. One of the possible DHEA(S) mechanisms is the modulation of brain-derived neurotrophic factor (BDNF) concentrations and tyrosine kinase receptors (Trk) for BDNF. Neurotrophin BDNF is also involved in synaptic plasticity and neuronal survival and reduced expression of BDNF in AD suggests its involvement in AD pathogenesis. However, the role of BDNF and DHEA(S), as well as their interaction in AD is not clear. Therefore, we have investigated the effects of DHEA(S) and BDNF in an in vitro model of AD with a particular focus on their interactions and their joint neuroprotective potential. Primary mouse neurons were treated with Aβ oligomers, as well as with DHEA(S) and BDNF or their combination. The obtained results suggest that DHEA(S) and BDNF may promise new options for the prevention and treatment of AD.
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- 2021
43. Neuroprotective effect of BDNF in an in vitro model of Alzheimer’s disease
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Vuić, Barbara, Nikolac Perković, Matea, Nedić Erjavec, Gordana, Tudor, Lucija, Konjevod, Marcela, Pivac, Nela, and Švob Štrac, Dubravka
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Aβ oligomers ,Alzheimer´s disease ,BDNF ,neuroprotection ,primary mouse neurons - Abstract
Alzheimer´s disease (AD) is a multifactorial neurodegenerative disorder still without effective and stable therapeutic strategies. It is characterized by the progressive cognitive decline and neuronal death, especially in the hippocampus and neocortex, which is probably due to the accumulation of beta amyloid (Aβ) plaques and neurofibrillary tangles. The etiology of AD is still not clear ; however, there are many known genetic and environmental risk factors. Brain- derived neurotrophic factor (BDNF) is the most widely distributed neurotrophic factor in the adult brain, whose levels are reduced in AD. BDNF plays an important role in synaptic plasticity, synaptogenesis, neuronal survival and growth, particullary in the hippocampus, the brain region essential for learning and memory. This study has investigated potential neuroprotective effect of BDNF in primary neuronal cultures derived from the C57BL/6 mice. Primary mouse neurons were treated with various concentrations of toxic Aβ oligomer preparations, as well as with different BDNF concentrations. The colorimetric MTT assay, Promega cell-based and biochemical assays and Muse cell analyzer were used to investigate Aβ-induced cytotoxicity, as well as neuroprotective effects of BDNF. The results demonstrated that Aβ oligomers caused necrosis and apoptosis of neuronal cells, rather than oxidative stress, presumably acting via membrane integrity disruption, as well as caspase and bcl-2 activation. The observed neuroprotective effect of BDNF alone, but also in the combination with neurosteroids dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) is, at least partly, achieved by blocking the caspase activation and suggests beneficial antiapoptotic actions of BDNF on the survival of neurons damaged in AD.
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- 2021
44. APOE genotype and essential metals in Alzheimer's disease
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Babić Leko, Mirjana, Jurasović, Jasna, Nikolac Perković, Matea, Španić, Ena, Sekovanić, Ankica, Orct, Tatjana, Lukinović Škudar, Vesna, Bačić Baronica, Koraljka, Kiđemet-Piskač, Spomenka, Vogrinc, Željka, Pivac, Nela, Borovečki, Fran, Hof, Patrick R., and Šimić, Goran
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Alzheimerova bolest ,metali ,apolipoprotein E ,cink ,bakar ,blagi spoznajni poremećaj - Abstract
Tijekom godina su nastale brojne hipoteze koje nastoje objasniti nastanak Alzheimerove bolesti (AB). Jedna od njih je hipoteza narušene homeostaze metala u mozgu oboljelih od AB. Ta hipoteza se uglavnom odnosi na metale koji su u normalnim okolnostima prisutni u organizmu i nužni su za funkcioniranje brojnih proteina i enzima. Gen za apolipoprotein E (ApoE), protein koji je uključen u transport kolesterola do neurona, glavni je genetički čimbenik rizika za nastanak sporadične AB. Cilj ovog istraživanja bio je istražiti potencijalnu povezanost ApoE i esencijalnih metala. Mjerili smo razine željeza, bakra, cinka, magnezija, natrija, kobalta, kalcija, mangana, molibdena, bora i kroma u likvoru i plazmi 126 osoba oboljelih od AB, 52 osobe s blagim spoznajnim poremećajem (BSP) i 19 zdravih kontrola s različitim APOE genetipovima. Rezultati su pokazali da su razine bakra, natrija i magnezija bile značajno povišene kod ispitanika s epsilon4 alelom. Razine natrija, kobalta i kalcija su bile značajno povišene u plazmi osoba s epsilon4 epsilonX genotipom. Razine bora mjerenog u plazmi su bile značajno snižene kod nositelja epsilon4 alela i epsilon4 epsilon4 genotipa. Dodatno su vrijednosti cinka i natrija mjerene u likvoru bile značajno povišene kod pacijenata s AB u odnosu na kontrole. Zaključno, rezultati ovog istraživanja upućuju na snažnu povezanost između APOE genotipa i koncentracija natrija, bakra, cinka, kalcija, magnezija, kobalta i metaloida bora mjerenih u plazmi osoba s AB i BSP.
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- 2021
45. DHEA, DHEAS i BDNF - potencijalne terapijske mete u Alzheimerovoj bolesti
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Vuić, Barbara, Nedić Erjavec, Gordana, Nikolac Perković, Matea, Tudor, Lucija, Konjevod, Marcela, Pivac, Nela, Erhardt, Julija, and Švob Štrac, Dubravka
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DHEA ,DHEAS ,BDNF ,Alzheimerova bolest ,neuroprotektivni učinak - Abstract
Cilj: Alzheimerova bolest (AB) je teška neurodegenerativna bolest i najčešći uzrok demencije, koji će u skoroj budućnosti zbog ubrzanog starenja stanovništva postati jedan od vodećih medicinskih, društvenih i ekonomskih problema. Terapija AB svodi se na simptomatsko liječenje, a brojne studije novih učinkovitih lijekova za sada su bezuspješne. Istraživanja pokazuju da neurosteroidi dehidroepiandrostendion (DHEA) i njegov sulfat (DHEAS), kao i neurotrofin moždani neurotrofni čimbenik (BDNF), posjeduju neuroprotektivno djelovanje i potencijal za prevenciju i liječenje AB. Međutim, njihove složene interakcije i molekularni mehanizmi djelovanja nisu u potpunosti razjašnjeni. Stoga je cilj ovog istraživanja poboljšati razumijevanje kompleksnih interakcija i mehanizama u podlozi terapijskog potencijala DHEA, DHEAS i BDNF u AB. Metode: In vitro istraživanja provedena su u primarnoj kulturi neurona, izoliranih iz embrija C57BL/6 miševa starih 15 dana. Stvaranje Aβ oligomera, koji se smatraju odgovornima za neurotoksični učinak u mozgu osoba s AB, provjereno je mikroskopijom atomskih sila (AFM) i denaturirajućom elektroforezom na poliakrilamidnom gelu (SDS-PAGE). Toksičnost Aβ oligomera u primarnoj kulturi neurona, kao i protektivni učinak tretmana s DHEA, DHEAS i BDNF, utvrđeni su kolorimetrijskim MTT testom i primjenom staničnog analizatora MUSE. Dobiveni rezultati obrađeni su u GraphPad Prism programu. Rezultati: Koncentracija preparacije Aβ oligomera od 10 μM primijenjena u trajanju od 24 sata optimalna je za izazivanje značajne toksičnosti u primarnoj kulturi neurona. S druge strane, koncentracije DHEA i DHEAS od 0, 1 μM i koncentracija od 100 ng/mL BDNF-a primijenjene u trajanju od 24 sata pokazale su najbolji neuroprotektivni učinak na neurone tretirane toksičnim Aβ oligomerima. Zaključak: Dobiveni rezultati upućuju na potencijalni neuroprotektivni učinak DHEA, DHEAS i BDNF-a u primarnoj kulturi mišjih neurona tretiranih toksičnim Aβ oligomerima. Međutim, potrebne su daljnje in vitro studije koja će razjasniti stanične i molekularne mehanizme njihovog neuroprotektivnog djelovanja, kao i istraživanja na mišjem modelu AB (3 x Tg-AD) i na uzorcima krvi oboljelih od AB, u svrhu potencijalne primjene tihneurosteroida i neurotrofina u ranom otkrivanju bolesti, kao i prevenciji i/ili liječenju simptoma AB.
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- 2021
46. Povezanost polimorfizma jednog nukleotida u genima za MAOB i APOE u Alzheimerovoj bolesti
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Babić Leko, Mirjana, Nikolac Perković, Matea, Nedić Erjavec, Gordana, Klepac, Nataša, Švob Štrac, Dubravka, Borovečki, Fran, Pivac, Nela, Hof, Patrick R., and Šimić, Goran
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Alzheimerova bolest ,APOE ,MAOB ,genetički biomarkeri ,polimorfizmi - Abstract
U tijeku Alzheimerove bolesti (AB) poremećeno je normalno funkcioniranje dopaminskog sustava, što se odnosi i na aktivnost monoaminooksidaze B (MAOB), enzima uključenog u razgradnju dopamina. Točnije, aktivnost MAOB je u AB-u povišena. Povećana ekspresija MAOB je uočena u hipokampusu i moždanoj kori osoba s AB-om. Primijećeno je da MAOB rs1799836 polimorfizam može utjecati na transkripciju MAOB te posljedično i na translaciju proteina te aktivnost MAOB. Naše je nedavno istraživanje pokazalo da je razina amiloida beta 1-42 mjerenog u likvoru bila značajno snižena kod nositelja A alela u MAOB rs1799836 polimorfizmu. Cilj ovog istraživanja je bila usporedba MAOB rs1799836 polimorfizma s APOE genotipom, jedinim potvrđenim genetičkim rizičnim čimbenikom za razvoj sporadične AB. Istraživanje je obuhvatilo 253 ispitanika, od koji je 127 bolovalo od AB, 57 su bili pacijenti s blagim spoznajnim poremećajem, 11 su bili zdrave kontrole, a 58 ih je bolovalo od drugih primarnih uzroka demencije. Rezultati su pokazali povišen broj pacijenata s APOE epsilon4/epsilon4 genotipom i nositelja APOE epsilon4 alela među nositeljima AA MAOB rs1799836 genotipa. Ti rezultati upućuju da bi MAOB rs1799836 polimorfizam mogao biti važan genetički biljen AB-a.
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- 2021
47. MAOB single nucleotide polymorphism as potential genetic biomarker of Alzheimer's disease
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Babić Leko, Mirjana, Nikolac Perković, Matea, Nedić Erjavec, Gordana, Klepac, Nataša, Švob Štrac, Dubravka, Borovečki, Fran, Pivac, Nela, Hof, Patrick R., Šimić, Goran, and Croatian Society for Neuroscience
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Alzheimer's disease ,apolipoprotein E ,genetic biomarker ,dopaminergic system ,monoamino oxidase B ,single nucleotide polymorphism - Abstract
The normal functioning of dopaminergic system is compromised during Alzheimer’s disease (AD). The activity of monoamine oxidase B (MAOB), enzyme involved in degradation of dopamine, is also disturbed in AD. It was observed that MAOB activity is increased during AD. Also, increased expression of MAOB was detected in hippocampus and cortex of people who suffered from AD. It was observed that MAOB rs1799836 polymorphism can affect MAOB transcription, consequently influencing also protein translation and MAOB activity. Our recent study showed that the levels of cerebrospinal fluid amyloid β1-42 were decreased in patients carrying A allele in MAOB rs1799836 polymorphism. The goal of this study was to compare MAOB rs1799836 polymorphism with APOE, the only confirmed genetic risk factor for sporadic AD. Study included 253 participants of whom 127 suffered from AD, 57 were mild cognitive impairment patients, 11 were healthy controls and 58 suffered from other primary causes of dementia. We observed that the number of APOE ɛ4/ɛ4 homozygotes and APOE ɛ4 carriers was significantly increased among patients carrying AA MAOB rs1799836 genotype. These results indicate that the MAOB rs1799836 polymorphism could be strong genetic biomarker of AD. Acknowledgements: Supported by The Croatian Science Foundation grant IP-2019-04-3584 (“Role of blood-brain barrier, innate immunity, and tau protein oligomerization in the pathogenesis of Alzheimer's disease”) to GŠ and by the Centre of Excellence for Basic, Clinical and Translational Neuroscience CoRE-NEURO (“Experimental and clinical research of hypoxic- ischemic damage in perinatal and adult brain” ; GA KK01.1.1.01.0007 funded by the European Union through the European Regional Development Fund)
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- 2021
48. Protective effects of dhea and dheas on sh-sy5y neuroblastoma cells and primary mouse neurons, exposed to aβ oligomers, hydrogen peroxide and oxygen-glucose deprivation, as in vitro models of dementia
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Vuić, Barbara, Nedić Erjavec, Gordana, Nikolac Perković, Matea, Tudor, Lucija, Konjevod, Marcela, Pivac, Nela, and Švob Štrac, Dubravka
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DHEA ,DHEAS ,Alzheimer´s disease ,vascular dementia ,primary mouse neurons ,SH-SY5Y cells - Abstract
Neurosteroids dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), the most abundant steroids in human blood, are also synthesized de novo in the brain, where they participate in varios functions such as neural plasticity, learning, memory and behavior. Dementia is a syndrome of progressive cognitive decline, with Alzheimer´s disease (AD) and vascular dementia (VaD), as the most common forms. AD is neurodegenerative disorder characterized by the abnormal deposition of the amyloid β (Aβ) peptide and accumulation of neurofibrillary tangles, and is associated with multiple pathophysiologic mechanisms including apoptosis and oxidative stress. VaD is due to the reduced blood flow, resulting in insufficient supply of nutrients and oxygen to the brain, leading to an impairment of memory and cognitive functions. We have investigated potential neuroprotective effects of these neurosteroids in primary mouse neurons, as well as in the SH-SY5Y neuroblastoma cells. As in vitro models of AD and VaD, we have exposed these cells to the toxic Aβ oligomers, hydrogen peroxide (H2O2) inducing oxidative stress, or to the oxygen-glucose deprivation (OGD). The obtained results demonstrated the beneficial effects of DHEA and DHEAS treatment on the cell survival and viability, suggesting potential neuroprotective actions of these neurosteroids in AD and VaD.
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- 2021
49. Childhood trauma types and symptom severity in Croatian war veterans suffering from posttraumatic stress disorder (PTSD)
- Author
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Jaksic, Nenad, Tudor, Lucija, Nedic Erjavec, Gordana, Nikolac Perkovic, Matea, Konjevod, Marcela, Svob Strac, Dubravka, Pivac, Nela, Uzun, Suzana, Kozumplik, Oliver, and Repovecki, Senka
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- 2020
- Full Text
- View/download PDF
50. IL-1β single nucleotide polymorphism as potential genetic biomarker of Alzheimer's disease
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Babić Leko, Mirjana, Nikolac Perković, Matea, Krbot Skorić, Magdalena, Klepac, Nataša, Vogrinc, Željka, Švob Štrac, Dubravka, Borovečki, Fran, Pivac, Nela, Hof, Patrick R., Šimić, Goran, Šimić, Goran, and Mimica, Ninoslav
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Alzheimer's disease ,biomarkers ,cerebrospinal fluid ,cytokines ,event-related potentials ,mild cognitive impairment ,Mini-Mental State Examination ,neuroflammation ,genetic polymorphisms - Abstract
Neuroinflammation commences years before Alzheimer's disease (AD). Its association with both amyloid and tau pathology is well documented. Activated microglia in the AD brain release pro- inflammatory cytokines that can damage neurons, while anti-inflammatory cytokines are also released to oppose this process. Association of IL-1β -1473C/G polymorphisms with AD was not previously documented. In this study we assessed whether people carrying certain genotype in this polymorphism have higher risk for AD. We tested the levels of cerebrospinal fluid (CSF) biomarkers, event-related potentials (ERP), and various neuropsychological tests between patients with different IL-1β -1473 genotype. After blood collection, isolation of DNA, and determination of polymorphisms, 157 subjects were tested neuropsychologically, including AD patients, mild cognitive impairment (MCI) patients, patients with other causes of dementia, and healthy controls. ERP were measured by electroencephalography (EEG) in cohort of 54 patients, while CSF biomarkers (amyloid β1-42 [Aβ1-42], total tau, phosphorylated tau proteins (at epitopes 181, 199 and 231) and visinin-like protein 1 [VILIP-1]) were measured by enzyme-linked immunosorbent assay (ELISA) in the group of 179 patients. A significant increase in total tau, p-tau199, p-tau231 and VILIP-1 CSF levels was found in carriers of a G allele in IL- 1β –1473C/G polymorphism. Also, P300 latency was significantly prolonged in patients carrying the G allele in the IL-1β -1473 polymorphism and carriers of G allele showed worse performance on various neuropsychological tests (Alzheimer’s disease assessment scale-Cog, California Verbal Learning Test, Clock drawing test, and modified Mini‐Mental State Examination [MMSE corrected for age and education]). In conclusion, IL-1β -1473 polymorphism may represent a strong genetic biomarker of AD since persons carrying G allele in this polymorphism could be more vulnerable to development of neuroinflammation, and consequently of AD.
- Published
- 2020
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