Goran Simic - Academia.edu (original) (raw)

Papers by Goran Simic

Alzheimers & Dementia, Jul 1, 2013

Journal of Clinical Medicine

Spinal muscular atrophy (SMA) is a progressive degenerative illness that affects 1 in every 6 to ... more Spinal muscular atrophy (SMA) is a progressive degenerative illness that affects 1 in every 6 to 11,000 live births. This autosomal recessive disorder is caused by homozygous deletion or mutation of the SMN1 gene (survival motor neuron). As a backup, the SMN1 gene has the SMN2 gene, which produces only 10% of the functional SMN protein. Nusinersen and risdiplam, the first FDA-approved medications, act as SMN2 pre-mRNA splicing modifiers and enhance the quantity of SMN protein produced by this gene. The emergence of new therapies for SMA has increased the demand for good prognostic and pharmacodynamic (response) biomarkers in SMA. This article discusses current molecular diagnostic, prognostic, and pharmacodynamic biomarkers that could be assessed in SMA patients’ body fluids. Although various proteomic, genetic, and epigenetic biomarkers have been explored in SMA patients, more research is needed to uncover new prognostic and pharmacodynamic biomarkers (or a combination of biomarkers).

Biomedicines

The role of metals in the pathogenesis of Alzheimer’s disease (AD) is still debated. Although pre... more The role of metals in the pathogenesis of Alzheimer’s disease (AD) is still debated. Although previous research has linked changes in essential metal homeostasis and exposure to environmental heavy metals to the pathogenesis of AD, more research is needed to determine the relationship between metals and AD. In this review, we included human studies that (1) compared the metal concentrations between AD patients and healthy controls, (2) correlated concentrations of AD cerebrospinal fluid (CSF) biomarkers with metal concentrations, and (3) used Mendelian randomization (MR) to assess the potential metal contributions to AD risk. Although many studies have examined various metals in dementia patients, understanding the dynamics of metals in these patients remains difficult due to considerable inconsistencies among the results of individual studies. The most consistent findings were for Zn and Cu, with most studies observing a decrease in Zn levels and an increase in Cu levels in AD pati...

Biomedicines

The tauopathy of Alzheimer’s disease (AD) is first observed in the brainstem and entorhinal corte... more The tauopathy of Alzheimer’s disease (AD) is first observed in the brainstem and entorhinal cortex, spreading trans-synaptically along specific pathways to other brain regions with recognizable patterns. Tau propagation occurs retrogradely and anterogradely (trans-synaptically) along a given pathway and through exosomes and microglial cells. Some aspects of in vivo tau spreading have been replicated in transgenic mice models expressing a mutated human MAPT (tau) gene and in wild-type mice. In this study, we aimed to characterize the propagation of different forms of tau species in non-transgenic 3–4 months old wild-type rats after a single unilateral injection of human tau oligomers and tau fibrils into the medial entorhinal cortex (mEC). We determined whether different variants of the inoculated human tau protein, tau fibrils, and tau oligomers, would induce similar neurofibrillary changes and propagate in an AD-related pattern, and how tau-related pathological changes would correl...

G. Simic , M. Babic Leko , D. Bazadona , V. Benkovic , M. Boban , F. Borovecki , A. Cirko , D. Di... more G. Simic , M. Babic Leko , D. Bazadona , V. Benkovic , M. Boban , F. Borovecki , A. Cirko , D. Dikic , M. Jazvinscak Jembrek , N. Klepac , N. Orsolic , Z. Petelin Gadze , P. Hof 6 University of Zagreb School of Medicine Croatian Institute for Brain Research, Department of Neuroscience, Zagreb, Croatia;University Clinical Hospital Zagreb, Department of Neurology, Zagreb, Croatia;University of Zagreb Faculty of Science, Department of Animal Physiology, Zagreb, Croatia;University of Zagreb School of Medicine, Department of Anatomy, Zagreb, Croatia;Ruder Boskovic Institute, Department for Molecular Medicine, Zagreb, Croatia;Icahn School of Medicine at Mount Sinai, Fishberg Department of Neuroscience, New York, USA.

Lijec̆nic̆ki vjesnik, 2010

Sa`etak. U Zagrebu je 12. prosinca 2009. odr`an simpozij »Dijete u suvremenome hrvatskom dru{tvu«... more Sa`etak. U Zagrebu je 12. prosinca 2009. odr`an simpozij »Dijete u suvremenome hrvatskom dru{tvu«, koji su organizirali Hrvatsko pedijatrijsko dru{tvo, Hrvatska akademija znanosti i umjetnosti, Ministarstvo zdravstva i socijalne skrbi i UNICEF za Hrvatsku. Predava~i su prikazali va`ne podatke o te{ko}ama kojima su izlo`ena djeca u Hrvatskoj. Naime, nove bolesti, koje su u suvremenom svijetu sve ~e{}e u djece, zahtijevaju od svih koji su uklju~eni u zdravstvenu za{titu djece nove pristupe radu, {to podrazumijeva i dodatnu edukaciju. To nisu bolesti uobi~ajene u svakodnevnoj lije~ni~koj praksi. Pristup dru{tva, zbog raznolikosti te{ko}a s kojima se djeca suo~avaju, mo`e biti samo multidisciplinaran. Temeljni nacionalni interes dru{tva je usmjeriti vi{e pozornosti i financijska sredstva na zdravstvenu za{titu djece, jer to osigurava opstanak i zdravu budu}nost dru{tva. Taj pristup zahtijeva nacionalni konsenzus i jasnu politi~ku odluku svih odgovornih slu`bi.

Molecular Psychiatry, 2021

Dementia and Geriatric Cognitive Disorders, 2012

Access to full text and tables of contents, including tentative ones for forthcoming issues: www.... more Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/dem_issues

Oxidative Medicine and Cellular Longevity, 2020

Copper, a transition metal with essential cellular functions, exerts neurotoxic effects when pres... more Copper, a transition metal with essential cellular functions, exerts neurotoxic effects when present in excess by promoting production of reactive oxygen species (ROS). The aim of the present study was to investigate potential benefits of flavonoid quercetin against copper-induced toxicity. Results obtained with MTT assay indicate that the effects of quercetin are determined by the severity of the toxic insult. In moderately injured P19 neuronal cells, concomitant treatment with 150 μM quercetin improved viability by preventing ROS formation, caspase-3 activation, and chromatin condensation. Western blot analysis revealed that quercetin reduced copper-induced increase in p53 upregulated modulator of apoptosis (PUMA) expression and promoted upregulation of nucleoside diphosphate kinase NME1. Levels of p53 and Bax proteins were not affected by both copper and quercetin. UO126 and wortmannin, inhibitors of ERK1/2 and PI3K/Akt signalling pathways, respectively, prevented neuroprotective...

A population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those... more A population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grownin vitrofrom non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss.Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-geneBACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21-organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (...

Background: Neuroinflammation is enhanced in Alzheimer’s disease (AD) brain. Its association with... more Background: Neuroinflammation is enhanced in Alzheimer’s disease (AD) brain. 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, IL-1α -889C/T and IL-10 -1082G/A polymorphisms with AD has been amply documented previously. In this study we assessed whether people carrying certain genotypes in these polymorphisms were more prone to disease progression as tested by the Mini‐Mental State Examination (MMSE) scores and event-related potentials (ERP). Methods: After blood collection, isolation of DNA and determination of polymorphisms, 226 subjects were tested neuropsychologically using MMSE (including AD patients, mild cognitive impairment patients, patients with other causes of dementia, and healthy controls). ERP were measured by electroencephalography (EEG) in this c...

Background Neuroinflammation plays an important role in Alzheimer’s disease (AD). During this pro... more Background Neuroinflammation plays an important role in Alzheimer’s disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor α (TNFα) that participate in neuron damage. However, anti-inflammatory cytokines (such as IL-10), which maintain homeostasis of immune response, are also released. Previous studies showed the association of IL-1α -889C/T (rs1800587), IL-1β -1473G/C (rs1143623), IL-6 -174C/G (rs1800795), IL-10 -1082G/A (rs1800896) and TNFα -308A/G (rs1800629) polymorphisms with AD.Methods In this study, we assessed whether people carrying certain genotypes in these polymorphisms are more prone to develop AD-related pathology, reflected by pathological levels of cerebrospinal fluid (CSF) AD biomarkers including amyloid β1–42 (Aβ1–42), total tau (t‐tau), tau phosphorylated at Thr 181 (p‐tau181), Ser 199 (p‐tau199), and Thr 231 (p‐tau231), and visinin‐like protein 1 (VILIP‐1). The s...

Journal of Comparative Neurology

Little is known about the development of the human entorhinal cortex (EC), a major hub in a wides... more Little is known about the development of the human entorhinal cortex (EC), a major hub in a widespread network for learning and memory, spatial navigation, high‐order processing of object information, multimodal integration, attention and awareness, emotion, motivation, and perception of time. We analyzed a series of 20 fetal and two adult human brains using Nissl stain, acetylcholinesterase (AChE) histochemistry, and immunocytochemistry for myelin basic protein (MBP), neuronal nuclei antigen (NeuN), a pan‐axonal neurofilament marker, and synaptophysin, as well as postmortem 3T MRI. In comparison with other parts of the cerebral cortex, the cytoarchitectural differentiation of the EC begins remarkably early, in the 10th week of gestation (w.g.). The differentiation occurs in a superficial magnocellular layer in the deep part of the marginal zone, accompanied by cortical plate (CP) condensation and multilayering of the deep part of CP. These processes last until the 13–14th w.g. At 1...

Socijalna psihijatrija, 2019

International Journal of Molecular Sciences

The extracellular matrix (ECM) is an important regulator of excitability and synaptic plasticity,... more The extracellular matrix (ECM) is an important regulator of excitability and synaptic plasticity, especially in its highly condensed form, the perineuronal nets (PNN). In patients with drug-resistant mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis type 1 (HS1) is the most common histopathological finding. This study aimed to evaluate the ECM profile of HS1 in surgically treated drug-resistant patients with MTLE in correlation to clinical findings. Hippocampal sections were immunohistochemically stained for aggrecan, neurocan, versican, chondroitin-sulfate (CS56), fibronectin, Wisteria floribunda agglutinin (WFA), a nuclear neuronal marker (NeuN), parvalbumin (PV), and glial-fibrillary-acidic-protein (GFAP). In HS1, besides the reduced number of neurons and astrogliosis, we found a significantly changed expression pattern of versican, neurocan, aggrecan, WFA-specific glycosylation, and a reduced number of PNNs. Patients with a lower number of epileptic episodes had a less...

Cells

Neuroinflammation is one of the core pathological features of Alzheimer’s disease (AD) as both am... more Neuroinflammation is one of the core pathological features of Alzheimer’s disease (AD) as both amyloid β (Aβ) and tau monomers and oligomers can trigger the long-term pro-inflammatory phenotype of microglial cells with consequent overactivation of the inflammasomes. To investigate the NLRP1 inflammasome activation in AD, we analyzed the expression of NLRP1, ASC, cleaved gasdermin (cGSDMD), and active caspase-6 (CASP-6) proteins in each hippocampal subdivision (hilar part of CA3, CA2/3, CA1, subiculum) of postmortem tissue of 9 cognitively healthy controls (HC) and 11 AD patients whose disease duration varied from 3 to 7 years after the clinical diagnosis. The total number of neurons, along with the total number of neurofibrillary tangles (NFTs), were estimated in Nissl- and adjacent modified Bielschowsky-stained sections, respectively, using the optical disector method. The same 9 HC and 11 AD cases were additionally semiquantitatively analyzed for expression of IBA1, HLA-DR, and CD...

Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased... more Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased levels of the SMN protein in subjects with proximal autosomal recessive spinal muscular atrophy (SMA), the exact sequence of pathological events leading to selective motoneuron cell death is not fully understood yet. In this review, new Wndings regarding the dual cellular role of the SMN protein (translocation of β-actin to axonal growth cones and snRNP biogenesis/pre-mRNA splicing) were integrated with recent data obtained by detailed neuropathological examination of SMA and control subjects. A presumptive series of 10 pathogenetic events for SMA is proposed as follows: (1) deletions or mutations of the SMN1 gene, (2) increased SMN mRNA decay and reduction in full-length functional SMN protein, (3) impaired motoneuron axonoand dendrogenesis, (4) failure of motoneurons to form synapses with corticospinal Wbers from upper motoneurons, (5) abnormal motoneuron migration towards ventral spi...

Current Alzheimer Research, 2021

Background: Sporadic Alzheimer’s Disease (AD) is assumed to be associated with different biologic... more Background: Sporadic Alzheimer’s Disease (AD) is assumed to be associated with different biological/genetic vulnerability, as well as with neuroinflammation, mediated by cytokines. The present study evaluated the role of cytokines in AD. Objective: The aim was to determine the possible association of TNF-α (rs1800629), IL1-α (rs1800587) and IL-10 (rs1800896) polymorphisms with AD, and to assess serum TNF-α, IL-1α and IL-10 concentrations in patients with AD and in subjects with mild cognitive impairment (MCI). Methods: The study included 645 Caucasian participants: 395 subjects with AD and 250 subjects with MCI. Genotyping was performed using real-time PCR in all 645 subjects, while serum concentrations of TNF-α, IL-1α and IL-10 and were determined using ELISA in 174 subjects. Results: The frequency of the TNF-α rs1800629, IL1-α rs1800587 or IL-10 rs1800896 genotypes did not differ significantly between patients with AD and MCI. Serum concentration of IL-1α and IL-10 were significan...

Molecular Neurodegeneration, 2020

Introduction Tau pathology is a major age-related event in Down syndrome with Alzheimer’s disease... more Introduction Tau pathology is a major age-related event in Down syndrome with Alzheimer’s disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue obtained postmortem for DS-AD cases. Here, we evaluated the binding characteristics of two Tau PET tracers (3H-MK6240 and 3H-THK5117) and one amyloid (3H-PIB) ligand in the medial frontal gyrus (MFG) and hippocampus (HIPP) in tissue from adults with DS-AD and DS cases with mild cognitive impairment (MCI) compared to sporadic AD. Methods Tau and amyloid autoradiography were performed on paraffin-embedded sections. To confirm respective ligand targets, adjacent sections were immunoreacted for phospho-Tau (AT8) and stained for amyloid staining using Amylo-Glo. Results The two Tau tracers showed a significant correlation with each other and wit...

Croatian Medical Journal, 2019

Alzheimers & Dementia, Jul 1, 2013

Journal of Clinical Medicine

Spinal muscular atrophy (SMA) is a progressive degenerative illness that affects 1 in every 6 to ... more Spinal muscular atrophy (SMA) is a progressive degenerative illness that affects 1 in every 6 to 11,000 live births. This autosomal recessive disorder is caused by homozygous deletion or mutation of the SMN1 gene (survival motor neuron). As a backup, the SMN1 gene has the SMN2 gene, which produces only 10% of the functional SMN protein. Nusinersen and risdiplam, the first FDA-approved medications, act as SMN2 pre-mRNA splicing modifiers and enhance the quantity of SMN protein produced by this gene. The emergence of new therapies for SMA has increased the demand for good prognostic and pharmacodynamic (response) biomarkers in SMA. This article discusses current molecular diagnostic, prognostic, and pharmacodynamic biomarkers that could be assessed in SMA patients’ body fluids. Although various proteomic, genetic, and epigenetic biomarkers have been explored in SMA patients, more research is needed to uncover new prognostic and pharmacodynamic biomarkers (or a combination of biomarkers).

Biomedicines

The role of metals in the pathogenesis of Alzheimer’s disease (AD) is still debated. Although pre... more The role of metals in the pathogenesis of Alzheimer’s disease (AD) is still debated. Although previous research has linked changes in essential metal homeostasis and exposure to environmental heavy metals to the pathogenesis of AD, more research is needed to determine the relationship between metals and AD. In this review, we included human studies that (1) compared the metal concentrations between AD patients and healthy controls, (2) correlated concentrations of AD cerebrospinal fluid (CSF) biomarkers with metal concentrations, and (3) used Mendelian randomization (MR) to assess the potential metal contributions to AD risk. Although many studies have examined various metals in dementia patients, understanding the dynamics of metals in these patients remains difficult due to considerable inconsistencies among the results of individual studies. The most consistent findings were for Zn and Cu, with most studies observing a decrease in Zn levels and an increase in Cu levels in AD pati...

Biomedicines

The tauopathy of Alzheimer’s disease (AD) is first observed in the brainstem and entorhinal corte... more The tauopathy of Alzheimer’s disease (AD) is first observed in the brainstem and entorhinal cortex, spreading trans-synaptically along specific pathways to other brain regions with recognizable patterns. Tau propagation occurs retrogradely and anterogradely (trans-synaptically) along a given pathway and through exosomes and microglial cells. Some aspects of in vivo tau spreading have been replicated in transgenic mice models expressing a mutated human MAPT (tau) gene and in wild-type mice. In this study, we aimed to characterize the propagation of different forms of tau species in non-transgenic 3–4 months old wild-type rats after a single unilateral injection of human tau oligomers and tau fibrils into the medial entorhinal cortex (mEC). We determined whether different variants of the inoculated human tau protein, tau fibrils, and tau oligomers, would induce similar neurofibrillary changes and propagate in an AD-related pattern, and how tau-related pathological changes would correl...

G. Simic , M. Babic Leko , D. Bazadona , V. Benkovic , M. Boban , F. Borovecki , A. Cirko , D. Di... more G. Simic , M. Babic Leko , D. Bazadona , V. Benkovic , M. Boban , F. Borovecki , A. Cirko , D. Dikic , M. Jazvinscak Jembrek , N. Klepac , N. Orsolic , Z. Petelin Gadze , P. Hof 6 University of Zagreb School of Medicine Croatian Institute for Brain Research, Department of Neuroscience, Zagreb, Croatia;University Clinical Hospital Zagreb, Department of Neurology, Zagreb, Croatia;University of Zagreb Faculty of Science, Department of Animal Physiology, Zagreb, Croatia;University of Zagreb School of Medicine, Department of Anatomy, Zagreb, Croatia;Ruder Boskovic Institute, Department for Molecular Medicine, Zagreb, Croatia;Icahn School of Medicine at Mount Sinai, Fishberg Department of Neuroscience, New York, USA.

Lijec̆nic̆ki vjesnik, 2010

Sa`etak. U Zagrebu je 12. prosinca 2009. odr`an simpozij »Dijete u suvremenome hrvatskom dru{tvu«... more Sa`etak. U Zagrebu je 12. prosinca 2009. odr`an simpozij »Dijete u suvremenome hrvatskom dru{tvu«, koji su organizirali Hrvatsko pedijatrijsko dru{tvo, Hrvatska akademija znanosti i umjetnosti, Ministarstvo zdravstva i socijalne skrbi i UNICEF za Hrvatsku. Predava~i su prikazali va`ne podatke o te{ko}ama kojima su izlo`ena djeca u Hrvatskoj. Naime, nove bolesti, koje su u suvremenom svijetu sve ~e{}e u djece, zahtijevaju od svih koji su uklju~eni u zdravstvenu za{titu djece nove pristupe radu, {to podrazumijeva i dodatnu edukaciju. To nisu bolesti uobi~ajene u svakodnevnoj lije~ni~koj praksi. Pristup dru{tva, zbog raznolikosti te{ko}a s kojima se djeca suo~avaju, mo`e biti samo multidisciplinaran. Temeljni nacionalni interes dru{tva je usmjeriti vi{e pozornosti i financijska sredstva na zdravstvenu za{titu djece, jer to osigurava opstanak i zdravu budu}nost dru{tva. Taj pristup zahtijeva nacionalni konsenzus i jasnu politi~ku odluku svih odgovornih slu`bi.

Molecular Psychiatry, 2021

Dementia and Geriatric Cognitive Disorders, 2012

Access to full text and tables of contents, including tentative ones for forthcoming issues: www.... more Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/dem_issues

Oxidative Medicine and Cellular Longevity, 2020

Copper, a transition metal with essential cellular functions, exerts neurotoxic effects when pres... more Copper, a transition metal with essential cellular functions, exerts neurotoxic effects when present in excess by promoting production of reactive oxygen species (ROS). The aim of the present study was to investigate potential benefits of flavonoid quercetin against copper-induced toxicity. Results obtained with MTT assay indicate that the effects of quercetin are determined by the severity of the toxic insult. In moderately injured P19 neuronal cells, concomitant treatment with 150 μM quercetin improved viability by preventing ROS formation, caspase-3 activation, and chromatin condensation. Western blot analysis revealed that quercetin reduced copper-induced increase in p53 upregulated modulator of apoptosis (PUMA) expression and promoted upregulation of nucleoside diphosphate kinase NME1. Levels of p53 and Bax proteins were not affected by both copper and quercetin. UO126 and wortmannin, inhibitors of ERK1/2 and PI3K/Akt signalling pathways, respectively, prevented neuroprotective...

A population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those... more A population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grownin vitrofrom non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss.Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-geneBACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21-organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (...

Background: Neuroinflammation is enhanced in Alzheimer’s disease (AD) brain. Its association with... more Background: Neuroinflammation is enhanced in Alzheimer’s disease (AD) brain. 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, IL-1α -889C/T and IL-10 -1082G/A polymorphisms with AD has been amply documented previously. In this study we assessed whether people carrying certain genotypes in these polymorphisms were more prone to disease progression as tested by the Mini‐Mental State Examination (MMSE) scores and event-related potentials (ERP). Methods: After blood collection, isolation of DNA and determination of polymorphisms, 226 subjects were tested neuropsychologically using MMSE (including AD patients, mild cognitive impairment patients, patients with other causes of dementia, and healthy controls). ERP were measured by electroencephalography (EEG) in this c...

Background Neuroinflammation plays an important role in Alzheimer’s disease (AD). During this pro... more Background Neuroinflammation plays an important role in Alzheimer’s disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor α (TNFα) that participate in neuron damage. However, anti-inflammatory cytokines (such as IL-10), which maintain homeostasis of immune response, are also released. Previous studies showed the association of IL-1α -889C/T (rs1800587), IL-1β -1473G/C (rs1143623), IL-6 -174C/G (rs1800795), IL-10 -1082G/A (rs1800896) and TNFα -308A/G (rs1800629) polymorphisms with AD.Methods In this study, we assessed whether people carrying certain genotypes in these polymorphisms are more prone to develop AD-related pathology, reflected by pathological levels of cerebrospinal fluid (CSF) AD biomarkers including amyloid β1–42 (Aβ1–42), total tau (t‐tau), tau phosphorylated at Thr 181 (p‐tau181), Ser 199 (p‐tau199), and Thr 231 (p‐tau231), and visinin‐like protein 1 (VILIP‐1). The s...

Journal of Comparative Neurology

Little is known about the development of the human entorhinal cortex (EC), a major hub in a wides... more Little is known about the development of the human entorhinal cortex (EC), a major hub in a widespread network for learning and memory, spatial navigation, high‐order processing of object information, multimodal integration, attention and awareness, emotion, motivation, and perception of time. We analyzed a series of 20 fetal and two adult human brains using Nissl stain, acetylcholinesterase (AChE) histochemistry, and immunocytochemistry for myelin basic protein (MBP), neuronal nuclei antigen (NeuN), a pan‐axonal neurofilament marker, and synaptophysin, as well as postmortem 3T MRI. In comparison with other parts of the cerebral cortex, the cytoarchitectural differentiation of the EC begins remarkably early, in the 10th week of gestation (w.g.). The differentiation occurs in a superficial magnocellular layer in the deep part of the marginal zone, accompanied by cortical plate (CP) condensation and multilayering of the deep part of CP. These processes last until the 13–14th w.g. At 1...

Socijalna psihijatrija, 2019

International Journal of Molecular Sciences

The extracellular matrix (ECM) is an important regulator of excitability and synaptic plasticity,... more The extracellular matrix (ECM) is an important regulator of excitability and synaptic plasticity, especially in its highly condensed form, the perineuronal nets (PNN). In patients with drug-resistant mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis type 1 (HS1) is the most common histopathological finding. This study aimed to evaluate the ECM profile of HS1 in surgically treated drug-resistant patients with MTLE in correlation to clinical findings. Hippocampal sections were immunohistochemically stained for aggrecan, neurocan, versican, chondroitin-sulfate (CS56), fibronectin, Wisteria floribunda agglutinin (WFA), a nuclear neuronal marker (NeuN), parvalbumin (PV), and glial-fibrillary-acidic-protein (GFAP). In HS1, besides the reduced number of neurons and astrogliosis, we found a significantly changed expression pattern of versican, neurocan, aggrecan, WFA-specific glycosylation, and a reduced number of PNNs. Patients with a lower number of epileptic episodes had a less...

Cells

Neuroinflammation is one of the core pathological features of Alzheimer’s disease (AD) as both am... more Neuroinflammation is one of the core pathological features of Alzheimer’s disease (AD) as both amyloid β (Aβ) and tau monomers and oligomers can trigger the long-term pro-inflammatory phenotype of microglial cells with consequent overactivation of the inflammasomes. To investigate the NLRP1 inflammasome activation in AD, we analyzed the expression of NLRP1, ASC, cleaved gasdermin (cGSDMD), and active caspase-6 (CASP-6) proteins in each hippocampal subdivision (hilar part of CA3, CA2/3, CA1, subiculum) of postmortem tissue of 9 cognitively healthy controls (HC) and 11 AD patients whose disease duration varied from 3 to 7 years after the clinical diagnosis. The total number of neurons, along with the total number of neurofibrillary tangles (NFTs), were estimated in Nissl- and adjacent modified Bielschowsky-stained sections, respectively, using the optical disector method. The same 9 HC and 11 AD cases were additionally semiquantitatively analyzed for expression of IBA1, HLA-DR, and CD...

Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased... more Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased levels of the SMN protein in subjects with proximal autosomal recessive spinal muscular atrophy (SMA), the exact sequence of pathological events leading to selective motoneuron cell death is not fully understood yet. In this review, new Wndings regarding the dual cellular role of the SMN protein (translocation of β-actin to axonal growth cones and snRNP biogenesis/pre-mRNA splicing) were integrated with recent data obtained by detailed neuropathological examination of SMA and control subjects. A presumptive series of 10 pathogenetic events for SMA is proposed as follows: (1) deletions or mutations of the SMN1 gene, (2) increased SMN mRNA decay and reduction in full-length functional SMN protein, (3) impaired motoneuron axonoand dendrogenesis, (4) failure of motoneurons to form synapses with corticospinal Wbers from upper motoneurons, (5) abnormal motoneuron migration towards ventral spi...

Current Alzheimer Research, 2021

Background: Sporadic Alzheimer’s Disease (AD) is assumed to be associated with different biologic... more Background: Sporadic Alzheimer’s Disease (AD) is assumed to be associated with different biological/genetic vulnerability, as well as with neuroinflammation, mediated by cytokines. The present study evaluated the role of cytokines in AD. Objective: The aim was to determine the possible association of TNF-α (rs1800629), IL1-α (rs1800587) and IL-10 (rs1800896) polymorphisms with AD, and to assess serum TNF-α, IL-1α and IL-10 concentrations in patients with AD and in subjects with mild cognitive impairment (MCI). Methods: The study included 645 Caucasian participants: 395 subjects with AD and 250 subjects with MCI. Genotyping was performed using real-time PCR in all 645 subjects, while serum concentrations of TNF-α, IL-1α and IL-10 and were determined using ELISA in 174 subjects. Results: The frequency of the TNF-α rs1800629, IL1-α rs1800587 or IL-10 rs1800896 genotypes did not differ significantly between patients with AD and MCI. Serum concentration of IL-1α and IL-10 were significan...

Molecular Neurodegeneration, 2020

Introduction Tau pathology is a major age-related event in Down syndrome with Alzheimer’s disease... more Introduction Tau pathology is a major age-related event in Down syndrome with Alzheimer’s disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue obtained postmortem for DS-AD cases. Here, we evaluated the binding characteristics of two Tau PET tracers (3H-MK6240 and 3H-THK5117) and one amyloid (3H-PIB) ligand in the medial frontal gyrus (MFG) and hippocampus (HIPP) in tissue from adults with DS-AD and DS cases with mild cognitive impairment (MCI) compared to sporadic AD. Methods Tau and amyloid autoradiography were performed on paraffin-embedded sections. To confirm respective ligand targets, adjacent sections were immunoreacted for phospho-Tau (AT8) and stained for amyloid staining using Amylo-Glo. Results The two Tau tracers showed a significant correlation with each other and wit...

Croatian Medical Journal, 2019