Diabetes mellitus and physiological adaptation to high blood glucose levels in animals

Dijabetes je bolest koja se razvija uslijed poremećaja metabolizma ugljikohidrata, masti i bjelančevina. Bolest karakteriziraju povišene koncentracije glukoze u krvi koje dovode do ozbiljnih komplikacija u organizmu. Upotrebom inzulina uspješno se kontroliraju razine glukoze ali nije u potpunosti riješen problem nastanka komplikacija za čiji je razvoj potreban dugi niz godina. U tu svrhu znanstvenici predlažu ptice kao modelne organizme za istraživanje bolesti. Među kralježnjacima, ptice imaju najveće razine glukoze u krvi i unatoč tome nemaju nikakvih posljedica. Posjeduju mehanizme kojima se uspješno bore protiv štetnih utjecaja hiperglikemije. Daljnje istraživanje tih mehanizama moglo bi promijeniti perspektivu liječenja dijabetesa.Diabetes is a disease that develops as a result of disorders in the metabolism of carbohydrates, lipids and proteins. Hyperglycaemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage of many organ systems. Allthough insulin is quite effective in controling blood glucose levels, serious complications can still occurre. Scientists propose birds as animal models for diabetes research. Birds have the highest blood glucose levels among the vertebrates, but without any consequences. They possess mechanisms that prevent development of complications caused by hyperglycemia. Further study of these mechanisms could change the perspective of diabetes treatment

Expression of activated microglia cells markers Iba1, CD68 and HLA-DR in the hippocampal formation of patients with Alzheimer's disease

Brojna istraživanja govore o štetnom utjecaju upalnih procesa i mikroglija stanica na razvoj Alzheimerove bolesti (AB). Stoga se u okviru diplomskog rada imunohistokemijskom metodom analizirao izražaj biljega prisutstva i aktivacije mikroglija stanica Iba1, CD68 i HLA-DR u uzorcima hipokampalne formacije zahvaćenim Alzheimerovom bolešću i kontrolnim uzorcima. Ciljevi istraživanja bili su ispitati izraženost biljega u područjima hipokampalne formacije (sloj zrnatih stanica nazubljene vijuge, hilus, CA3/2, CA1, subikul, bijela tvar), utvrditi postoji li pozitivna korelacija izražaja biljega s duljinom trajanja AB i usporediti izražaj biljega aktivirane mikroglije, CD68 i HLA-DR s brojem amiloidnih plakova i neurofibrilarnih snopića u područjima hipokampalne formacije. Istraživanje je pokazalo da se izražaj biljega mikroglija stanica razlikuje u mozgu osoba oboljelih od AB i kontrolnih ispitanika. Pronađena je pozitivna korelacija izražaja biljega aktivirane mikroglije, CD68 i HLA-DR s pojavom AB i njihov povećani izražaj u područjima hipokampalne formacije koja su najviše zahvaćena patologijom AB, te negativna korelacija izražaja Iba1 s AB. Dobiveni rezultati podupiru hipoteze o ulozi upale u neurodegenerativnim bolestima i štetnom utjecaju mikroglija stanica u AB.Numerous studies indicate the harmful effect of inflammatory processes and microglia cells in Alzheimer's disease (AD). Therefore, within the graduate thesis, we analyzed expression of microglia cells markers Iba1, CD68 and HLA-DR in the hippocampal formation of patients with Alzheimer's disease and control samples. The main goals were to determine expression of markers in the different areas of hippocampal formation (granular cell layer of dentate gyrus, hilus, CA2/3, CA1, subiculum and white matter), to determine whether there is a positive correlation between expression of the markers and the duration of AD and to compare the expression of activated microglia cells markers, CD68 and HLA-DR with numbers of amyloid plaques and neurofibrillary tangles in different areas of hippocampal formation. The research has shown that the expression of microglia markers differs in the AD brains and controls. There was a positive correlation between expression of activated microglia cells markers CD68 and HLA-DR with the AD and their higher expression in the areas of hippocampal formation most affected by AD pathology and the negative correlation of expression of Iba1 with the AD. These results support the inflammatory hypothesis of neurodegenerative diseases and the harmful effect of the microglia cells in the AD

Expression of activated microglia cells markers Iba1, CD68 and HLA-DR in the hippocampal formation of patients with Alzheimer's disease

Brojna istraživanja govore o štetnom utjecaju upalnih procesa i mikroglija stanica na razvoj Alzheimerove bolesti (AB). Stoga se u okviru diplomskog rada imunohistokemijskom metodom analizirao izražaj biljega prisutstva i aktivacije mikroglija stanica Iba1, CD68 i HLA-DR u uzorcima hipokampalne formacije zahvaćenim Alzheimerovom bolešću i kontrolnim uzorcima. Ciljevi istraživanja bili su ispitati izraženost biljega u područjima hipokampalne formacije (sloj zrnatih stanica nazubljene vijuge, hilus, CA3/2, CA1, subikul, bijela tvar), utvrditi postoji li pozitivna korelacija izražaja biljega s duljinom trajanja AB i usporediti izražaj biljega aktivirane mikroglije, CD68 i HLA-DR s brojem amiloidnih plakova i neurofibrilarnih snopića u područjima hipokampalne formacije. Istraživanje je pokazalo da se izražaj biljega mikroglija stanica razlikuje u mozgu osoba oboljelih od AB i kontrolnih ispitanika. Pronađena je pozitivna korelacija izražaja biljega aktivirane mikroglije, CD68 i HLA-DR s pojavom AB i njihov povećani izražaj u područjima hipokampalne formacije koja su najviše zahvaćena patologijom AB, te negativna korelacija izražaja Iba1 s AB. Dobiveni rezultati podupiru hipoteze o ulozi upale u neurodegenerativnim bolestima i štetnom utjecaju mikroglija stanica u AB.Numerous studies indicate the harmful effect of inflammatory processes and microglia cells in Alzheimer's disease (AD). Therefore, within the graduate thesis, we analyzed expression of microglia cells markers Iba1, CD68 and HLA-DR in the hippocampal formation of patients with Alzheimer's disease and control samples. The main goals were to determine expression of markers in the different areas of hippocampal formation (granular cell layer of dentate gyrus, hilus, CA2/3, CA1, subiculum and white matter), to determine whether there is a positive correlation between expression of the markers and the duration of AD and to compare the expression of activated microglia cells markers, CD68 and HLA-DR with numbers of amyloid plaques and neurofibrillary tangles in different areas of hippocampal formation. The research has shown that the expression of microglia markers differs in the AD brains and controls. There was a positive correlation between expression of activated microglia cells markers CD68 and HLA-DR with the AD and their higher expression in the areas of hippocampal formation most affected by AD pathology and the negative correlation of expression of Iba1 with the AD. These results support the inflammatory hypothesis of neurodegenerative diseases and the harmful effect of the microglia cells in the AD

Understanding emotions: origins and roles of the amygdala

Emotions arise from activations of specialized neuronal populations in several parts of the cerebral cortex, notably the anterior cingulate, insula, ventromedial prefrontal, and subcortical structures, such as the amygdala, ventral striatum, putamen, caudate nucleus, and ventral tegmental area. Feelings are conscious, emotional experiences of these activations that contribute to neuronal networks mediating thoughts, language, and behavior, thus enhancing the ability to predict, learn, and reappraise stimuli and situations in the environment based on previous experiences. Contemporary theories of emotion converge around the key role of the amygdala as the central subcortical emotional brain structure that constantly evaluates and integrates a variety of sensory information from the surroundings and assigns them appropriate values of emotional dimensions, such as valence, intensity, and approachability. The amygdala participates in the regulation of autonomic and endocrine functions, decision-making and adaptations of instinctive and motivational behaviors to changes in the environment through implicit associative learning, changes in short- and long-term synaptic plasticity, and activation of the fight-or-flight response via efferent projections from its central nucleus to cortical and subcortical structures

Increased NLRP1 mRNA and Protein Expression Suggests Inflammasome Activation in the Dorsolateral Prefrontal and Medial Orbitofrontal Cortex in Schizophrenia

Schizophrenia is a complex mental condition, with key symptoms marked for diagnosis including delusions, hallucinations, disorganized thinking, reduced emotional expression, and social dysfunction. In the context of major developmental hypotheses of schizophrenia, notably those concerning maternal immune activation and neuroinflammation, we studied NLRP1 expression and content in the postmortem brain tissue of 10 schizophrenia and 10 control subjects. In the medial orbitofrontal cortex (Brodmann’s area 11/12) and dorsolateral prefrontal cortex (area 46) from both hemispheres of six schizophrenia subjects, the NLRP1 mRNA expression was significantly higher than in six control brains (p < 0.05). As the expression difference was highest for the medial orbitofrontal cortex in the right hemisphere, we assessed NLRP1-immunoreactive pyramidal neurons in layers III, V, and VI in the medial orbitofrontal cortex in the right hemisphere of seven schizophrenia and five control brains. Compared to controls, we quantified a significantly higher number of NLRP1-positive pyramidal neurons in the schizophrenia brains (p < 0.01), suggesting NLRP1 inflammasome activation in schizophrenia subjects. Layer III pyramidal neuron dysfunction aligns with working memory deficits, while impairments of pyramidal neurons in layers V and VI likely disrupt predictive processing. We propose NLRP1 inflammasome as a potential biomarker and therapeutic target in schizophrenia

Expression of activated microglia cells markers Iba1, CD68 and HLA-DR in the hippocampal formation of patients with Alzheimer's disease

Brojna istraživanja govore o štetnom utjecaju upalnih procesa i mikroglija stanica na razvoj Alzheimerove bolesti (AB). Stoga se u okviru diplomskog rada imunohistokemijskom metodom analizirao izražaj biljega prisutstva i aktivacije mikroglija stanica Iba1, CD68 i HLA-DR u uzorcima hipokampalne formacije zahvaćenim Alzheimerovom bolešću i kontrolnim uzorcima. Ciljevi istraživanja bili su ispitati izraženost biljega u područjima hipokampalne formacije (sloj zrnatih stanica nazubljene vijuge, hilus, CA3/2, CA1, subikul, bijela tvar), utvrditi postoji li pozitivna korelacija izražaja biljega s duljinom trajanja AB i usporediti izražaj biljega aktivirane mikroglije, CD68 i HLA-DR s brojem amiloidnih plakova i neurofibrilarnih snopića u područjima hipokampalne formacije. Istraživanje je pokazalo da se izražaj biljega mikroglija stanica razlikuje u mozgu osoba oboljelih od AB i kontrolnih ispitanika. Pronađena je pozitivna korelacija izražaja biljega aktivirane mikroglije, CD68 i HLA-DR s pojavom AB i njihov povećani izražaj u područjima hipokampalne formacije koja su najviše zahvaćena patologijom AB, te negativna korelacija izražaja Iba1 s AB. Dobiveni rezultati podupiru hipoteze o ulozi upale u neurodegenerativnim bolestima i štetnom utjecaju mikroglija stanica u AB.Numerous studies indicate the harmful effect of inflammatory processes and microglia cells in Alzheimer's disease (AD). Therefore, within the graduate thesis, we analyzed expression of microglia cells markers Iba1, CD68 and HLA-DR in the hippocampal formation of patients with Alzheimer's disease and control samples. The main goals were to determine expression of markers in the different areas of hippocampal formation (granular cell layer of dentate gyrus, hilus, CA2/3, CA1, subiculum and white matter), to determine whether there is a positive correlation between expression of the markers and the duration of AD and to compare the expression of activated microglia cells markers, CD68 and HLA-DR with numbers of amyloid plaques and neurofibrillary tangles in different areas of hippocampal formation. The research has shown that the expression of microglia markers differs in the AD brains and controls. There was a positive correlation between expression of activated microglia cells markers CD68 and HLA-DR with the AD and their higher expression in the areas of hippocampal formation most affected by AD pathology and the negative correlation of expression of Iba1 with the AD. These results support the inflammatory hypothesis of neurodegenerative diseases and the harmful effect of the microglia cells in the AD

Association of biomarkers of Alzheimer’s disease with inflammatory mediators and activation of microglia and inflammasome

Neprimjerena aktivacija mikroglije implicirana je u patogenezi Alzheimerove bolesti (AD), ali nije poznato kako dovodi do disfunkcije neurona i spoznajnog urušavanja. Da bismo bolje razjasnili ulogu upalnih procesa u nastanku i progresiji AD-a, pomoću ELISA i multipleks ELISA metode mjerili smo koncentracije imunosnih medijatora i biljega aktivacije mikroglije (sTREM2) i inflamasoma (ASC) u cerebrospinalnoj tekućini (CSF) i plazmi uzoraka izuzetih od osoba s AD-om, blagim spoznajnim poremećajem (MCI) i kognitivno zdravih kontrolnih ispitanika (HC). Dodatno, korištenjem metoda imunohistokemijskog bojenja postmortalnog tkiva mozgova osoba s AD-om i HC-a analizirali smo aktivaciju mikroglije i izraženost inflamasoma. Rezultati su pokazali jaču aktivaciju mikroglije i NLRP1 inflamasoma u hipokampalnoj formaciji osoba s AD-om. Analizom likvorskih biljega utvrđene su veće koncentracije sTREM2 i ASC u bolesnika s AD-om, ako i njihova pozitivna korelacija s biljezima neurodegenerativnih i neurofibrilarnih promjena. Likvor bolesnika s AD-om imao je jasan proupalni profil i povećane koncentracije medijatora stečene imunosti. Zaključno, ova je studija pokazala snažniji imunosni odgovor u bolesnika s AD-om, veću uključenost mehanizama stečene imunosti i visoku korelaciju između aktivacije imunološkog sustava i razvoja neurofibrilarnih promjena.Aberrant microglial activation has been implicated in the pathogenesis of Alzheimer’s disease (AD), but how it leads to neuronal dysfunction and cognitive decline is not known. To better clarify the role of inflammatory processes in the development and progression of AD, using ELISA and multiplex ELISA method we measured concentrations of the immune mediators and markers of microglial (sTREM2) and inflammasome (ASC) activation in cerebrospinal fluid (CSF) and plasma samples of AD, mild cognitive impairment, and cognitively healthy control subjects (HC). We also analysed microglial and inflammasome activation using immunohistochemical staining methods in postmortal human brain tissue of the AD and HC subjects. The results have shown stronger microglial and NLRP1 inflammasome activation in the hippocampal formation of the AD subjects. Analysis of the CSF markers has shown higher concentrations of sTREM2 and ASC in patients with AD and their positive correlations with markers of neurodegenerative and tau pathological changes. The CSF of AD patients has a pro-inflammatory profile and increased concentrations of mediators of adaptive immunity. Taken together, this study has shown a stronger immune response in AD patients, higher involvement of adaptive immunity mechanisms, and a high correlation between the activation of the immune system and the development of neurofibrillary changes

Association of biomarkers of Alzheimer’s disease with inflammatory mediators and activation of microglia and inflammasome

Neprimjerena aktivacija mikroglije implicirana je u patogenezi Alzheimerove bolesti (AD), ali nije poznato kako dovodi do disfunkcije neurona i spoznajnog urušavanja. Da bismo bolje razjasnili ulogu upalnih procesa u nastanku i progresiji AD-a, pomoću ELISA i multipleks ELISA metode mjerili smo koncentracije imunosnih medijatora i biljega aktivacije mikroglije (sTREM2) i inflamasoma (ASC) u cerebrospinalnoj tekućini (CSF) i plazmi uzoraka izuzetih od osoba s AD-om, blagim spoznajnim poremećajem (MCI) i kognitivno zdravih kontrolnih ispitanika (HC). Dodatno, korištenjem metoda imunohistokemijskog bojenja postmortalnog tkiva mozgova osoba s AD-om i HC-a analizirali smo aktivaciju mikroglije i izraženost inflamasoma. Rezultati su pokazali jaču aktivaciju mikroglije i NLRP1 inflamasoma u hipokampalnoj formaciji osoba s AD-om. Analizom likvorskih biljega utvrđene su veće koncentracije sTREM2 i ASC u bolesnika s AD-om, ako i njihova pozitivna korelacija s biljezima neurodegenerativnih i neurofibrilarnih promjena. Likvor bolesnika s AD-om imao je jasan proupalni profil i povećane koncentracije medijatora stečene imunosti. Zaključno, ova je studija pokazala snažniji imunosni odgovor u bolesnika s AD-om, veću uključenost mehanizama stečene imunosti i visoku korelaciju između aktivacije imunološkog sustava i razvoja neurofibrilarnih promjena.Aberrant microglial activation has been implicated in the pathogenesis of Alzheimer’s disease (AD), but how it leads to neuronal dysfunction and cognitive decline is not known. To better clarify the role of inflammatory processes in the development and progression of AD, using ELISA and multiplex ELISA method we measured concentrations of the immune mediators and markers of microglial (sTREM2) and inflammasome (ASC) activation in cerebrospinal fluid (CSF) and plasma samples of AD, mild cognitive impairment, and cognitively healthy control subjects (HC). We also analysed microglial and inflammasome activation using immunohistochemical staining methods in postmortal human brain tissue of the AD and HC subjects. The results have shown stronger microglial and NLRP1 inflammasome activation in the hippocampal formation of the AD subjects. Analysis of the CSF markers has shown higher concentrations of sTREM2 and ASC in patients with AD and their positive correlations with markers of neurodegenerative and tau pathological changes. The CSF of AD patients has a pro-inflammatory profile and increased concentrations of mediators of adaptive immunity. Taken together, this study has shown a stronger immune response in AD patients, higher involvement of adaptive immunity mechanisms, and a high correlation between the activation of the immune system and the development of neurofibrillary changes

Association of biomarkers of Alzheimer’s disease with inflammatory mediators and activation of microglia and inflammasome

Neprimjerena aktivacija mikroglije implicirana je u patogenezi Alzheimerove bolesti (AD), ali nije poznato kako dovodi do disfunkcije neurona i spoznajnog urušavanja. Da bismo bolje razjasnili ulogu upalnih procesa u nastanku i progresiji AD-a, pomoću ELISA i multipleks ELISA metode mjerili smo koncentracije imunosnih medijatora i biljega aktivacije mikroglije (sTREM2) i inflamasoma (ASC) u cerebrospinalnoj tekućini (CSF) i plazmi uzoraka izuzetih od osoba s AD-om, blagim spoznajnim poremećajem (MCI) i kognitivno zdravih kontrolnih ispitanika (HC). Dodatno, korištenjem metoda imunohistokemijskog bojenja postmortalnog tkiva mozgova osoba s AD-om i HC-a analizirali smo aktivaciju mikroglije i izraženost inflamasoma. Rezultati su pokazali jaču aktivaciju mikroglije i NLRP1 inflamasoma u hipokampalnoj formaciji osoba s AD-om. Analizom likvorskih biljega utvrđene su veće koncentracije sTREM2 i ASC u bolesnika s AD-om, ako i njihova pozitivna korelacija s biljezima neurodegenerativnih i neurofibrilarnih promjena. Likvor bolesnika s AD-om imao je jasan proupalni profil i povećane koncentracije medijatora stečene imunosti. Zaključno, ova je studija pokazala snažniji imunosni odgovor u bolesnika s AD-om, veću uključenost mehanizama stečene imunosti i visoku korelaciju između aktivacije imunološkog sustava i razvoja neurofibrilarnih promjena.Aberrant microglial activation has been implicated in the pathogenesis of Alzheimer’s disease (AD), but how it leads to neuronal dysfunction and cognitive decline is not known. To better clarify the role of inflammatory processes in the development and progression of AD, using ELISA and multiplex ELISA method we measured concentrations of the immune mediators and markers of microglial (sTREM2) and inflammasome (ASC) activation in cerebrospinal fluid (CSF) and plasma samples of AD, mild cognitive impairment, and cognitively healthy control subjects (HC). We also analysed microglial and inflammasome activation using immunohistochemical staining methods in postmortal human brain tissue of the AD and HC subjects. The results have shown stronger microglial and NLRP1 inflammasome activation in the hippocampal formation of the AD subjects. Analysis of the CSF markers has shown higher concentrations of sTREM2 and ASC in patients with AD and their positive correlations with markers of neurodegenerative and tau pathological changes. The CSF of AD patients has a pro-inflammatory profile and increased concentrations of mediators of adaptive immunity. Taken together, this study has shown a stronger immune response in AD patients, higher involvement of adaptive immunity mechanisms, and a high correlation between the activation of the immune system and the development of neurofibrillary changes

Role of Microglial Cells in Alzheimer’s Disease Tau Propagation

Uncontrolled immune response in the brain contributes to the progression of all neurodegenerative disease, including Alzheimer's disease (AD). Recent investigations have documented the prion-like features of tau protein and the involvement of microglial changes with tau pathology. While it is still unclear what sequence of events is causal, it is likely that tau seeding potential and microglial contribution to tau propagation act together, and are essential for the development and progression of degenerative changes. Based on available evidence, targeting tau seeds and controlling some signaling pathways in a complex inflammation process could represent a possible new therapeutic approach for treating neurodegenerative diseases. Recent findings propose novel diagnostic assays and markers that may be used together with standard methods to complete and improve the diagnosis and classification of these diseases. In conclusion, a novel perspective on microglia-tau relations reveals new issues to investigate and imposes different approaches for developing therapeutic strategies for AD