المؤلفون: E. De Vita, Rachael I. Scahill, Filipe B. Rodrigues, R. Tortelli, Mariette Heins, Gunnar Flik, A. J. Lowe, Lauren M. Byrne, Flaviano Giorgini, Eileanoir B. Johnson, Edward J. Wild

المصدر: Journal of Neurochemistry

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Kynurenine pathway, Pharmacology, Biochemistry, cerebrospinal fluid, Cohort Studies, Pathogenesis, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Kynurenic acid, Cerebrospinal fluid, Huntington's disease, blood, medicine, Humans, Prospective Studies, Kynurenine, Chromatography, High Pressure Liquid, Aged, business.industry, Clinical Studies, Biomakers & Imaging, biomarkers, Human brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Huntington Disease, Phenotype, 030104 developmental biology, medicine.anatomical_structure, chemistry, Original Article, Female, ORIGINAL ARTICLES, business, 030217 neurology & neurosurgery, Signal Transduction, Quinolinic acid

الوصف: Converging lines of evidence from several models, and post‐mortem human brain tissue studies, support the involvement of the kynurenine pathway (KP) in Huntington's disease (HD) pathogenesis. Quantifying KP metabolites in HD biofluids is desirable, both to study pathobiology and as a potential source of biomarkers to quantify pathway dysfunction and evaluate the biochemical impact of therapeutic interventions targeting its components. In a prospective single‐site controlled cohort study with standardised collection of cerebrospinal fluid (CSF), blood, phenotypic and imaging data, we used high‐performance liquid‐chromatography to measure the levels of KP metabolites—tryptophan, kynurenine, kynurenic acid, 3‐hydroxykynurenine, anthranilic acid and quinolinic acid—in CSF and plasma of 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD). We investigated short‐term stability, intergroup differences, associations with clinical and imaging measures and derived sample‐size calculation for future studies. Overall, KP metabolites in CSF and plasma were stable over 6 weeks, displayed no significant group differences and were not associated with clinical or imaging measures. We conclude that the studied metabolites are readily and reliably quantifiable in both biofluids in controls and HD gene expansion carriers. However, we found little evidence to support a substantial derangement of the KP in HD, at least to the extent that it is reflected by the levels of the metabolites in patient‐derived biofluids.
Converging lines of evidence from non‐human models support the involvement of the kynurenine pathway in Huntington's disease. However, evidence in living humans is limited. In a prospective study with standardised collection of cerebrospinal fluid and blood, we used high‐performance liquid‐chromatography to analyse this pathway. We concluded that the selected metabolites are readily and reliably quantifiable. Yet, we found little evidence to support a substantial derangement of the kynurenine pathway in Huntington's disease, at least to the extent that it is reflected by the levels of the metabolites in patient‐derived biofluids. 3‐HK, 3‐hydroxykynurenine; KYNA, kynurenic acid; QUIN, quinolinic acid.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6eaf51725f7f138eabd61f8be52c8ce9Test
https://doi.org/10.1111/jnc.15360Test

المؤلفون: Gene J. Blatt, Cheryl Brandenburg

المصدر: Journal of Neurochemistry

مصطلحات موضوعية: Male, 0301 basic medicine, Autism Spectrum Disorder, Biochemistry, 0302 clinical medicine, Cortex (anatomy), Medicine, Child, Serotonin transporter, Serotonin Plasma Membrane Transport Proteins, biology, Clinical Studies, Biomakers & Imaging, Brain, 3. Good health, anterior cingulate cortex, medicine.anatomical_structure, Original Article, Female, Selective Serotonin Reuptake Inhibitors, Neurotypical, Adult, medicine.medical_specialty, Adolescent, Serotonin reuptake inhibitor, autism, selective serotonin reuptake inhibitors (SSRIs), behavioral disciplines and activities, serotonin receptors (5‐HT2, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, 5‐HT1A), Internal medicine, mental disorders, Humans, Anterior cingulate cortex, 5-HT receptor, business.industry, serotonin transporter (5‐HTT), medicine.disease, 030104 developmental biology, Endocrinology, nervous system, Posterior cingulate, biology.protein, Autism, ORIGINAL ARTICLES, Receptors, Serotonin, 5-HT2, business, 030217 neurology & neurosurgery

الوصف: As selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications in autism, we aimed to determine whether targets for SSRIs are differentially affected in three cortical areas in children and adults with autism compared to neurotypical individuals. Utilizing a large cohort of postmortem brain tissue (n = 14–19 per group), saturation ligand binding assays were conducted on sections from the anterior cingulate cortex (ACC), posterior cingulate cortex, and fusiform gyrus (FG). Specific binding to the 5‐HT transporter (5‐HTT) as well as to 5‐HT2 and 1A receptors (5‐HT₂, 5‐HT1A) was quantified in superficial and deep layers of each region using the ligands [3H]‐citalopram (5‐HTT), [3H]‐ketanserin (5‐HT2), and [3H]‐8‐OH‐DPAT (5‐HT1A). A Welch’s t‐test was utilized to compare receptor densities (B max), revealing a statistically significant decrease in 5‐HTT within the ACC of the entire autism cohort. There was also a decrease in 5‐HT2 receptor density in the ACC in the adult cohort, but not in child postmortem autism cases as compared to controls. Comparing linear regression lines of B max values plotted against age, shows a significantly lower intercept for 5‐HTT in autism (p = 0.025). 5‐HT₂ density increases with age in control cases, whereas in autism there is a decrease with age and significantly different slopes between regression lines (p = 0.032). This suggests a deficit in 5‐HTT within the ACC in individuals with autism, while decreases in 5‐HT₂ density are age‐dependent. There were no differences in receptor densities in the posterior cingulate cortex or FG in autism and no differences in ligand affinity (K D) across all regions and ligands examined.
Although selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications in autism, several studies show variable efficacy with SSRI use. Some of this variability may be a result of differential expression of serotonin receptors across individuals. The objective of this study was to determine differences in density and/or affinity of the serotonin transporter (5‐HTT), serotonin 2 receptor (5‐HT2) and serotonin 1A receptor (5‐HT1A) between autism and neurotypical individuals through saturation binding assays within three cortical areas. Our findings support the growing evidence for caution when administering SSRIs to children, while adults may benefit from these treatments.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a1a9b8d8b791a521f5c812b27d26c682Test
https://doi.org/10.1111/jnc.14832Test

المؤلفون: Kaj Blennow, Tammaryn Lashley, Bruno Becker, Elena Camporesi, Faisal Hayat Nazir, Hlin Kvartsberg, Henrik Zetterberg, Christina E. Toomey, Gunnar Brinkmalm

المصدر: Journal of Neurochemistry

مصطلحات موضوعية: 0301 basic medicine, Calmodulin, Immunoprecipitation, Size-exclusion chromatography, Immunoblotting, heparin‐binding motif, Ultrafiltration, Enzyme-Linked Immunosorbent Assay, CSF, Cleavage (embryo), Biochemistry, Mass Spectrometry, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Cerebrospinal fluid, Humans, Neurogranin, Amino Acid Sequence, chemistry.chemical_classification, Brain Chemistry, biology, Molecular Structure, neurogranin, Heparin, Clinical Studies, Biomakers & Imaging, Phosphatidic acid, Molecular biology, Amino acid, Molecular Weight, 030104 developmental biology, chemistry, biology.protein, Chromatography, Gel, Original Article, ORIGINAL ARTICLES, 030217 neurology & neurosurgery, Protein Binding

الوصف: Neurogranin (Ng) is a 78 amino acid neuronal protein and a biomarker candidate for Alzheimer's disease (AD). Ng has been suggested to bind to calmodulin and phosphatidic acid via its centrally located IQ domain. Ng is cleaved within this functionally important domain, yielding the majority of fragments identified in cerebrospinal fluid (CSF), suggesting that cleavage of Ng may be a mechanism to regulate its function. Up to now, Ng has been shown to be present in CSF as both C‐terminal fragments as well as full‐length protein. To obtain an overview of the different molecular forms of Ng present in CSF, we show by size exclusion chromatography (SEC), immunoblotting, immunoprecipitation, and MS that Ng is present in CSF as several molecular forms. Besides monomeric full‐length Ng, also higher molecular weight forms of Ng, and C‐terminal‐ and previously not identified N‐terminal fragments were observed. We found by immunodepletion that C‐terminal peptides contribute on average to ~50% of the total‐Ng ELISA signal in CSF samples. There were no differences in the overall C‐terminal fragment/total‐Ng ratios between samples from AD and control groups. In addition, we found that monomeric Ng and its C‐terminal fragments bind to heparin via a heparin‐binding motif, which might be of relevance for their export mechanism from neurons. Taken together, this study highlights the presence of several molecular forms of Ng in CSF, comprising monomeric full‐length Ng, and N‐ and C‐terminal truncations of Ng, as well as larger forms of still unknown composition.
C‐terminal fragments, along with full‐length forms of neurogranin (Ng) have been previously found at higher concentration in CSF from Alzheimer´s disease patients. Calpain 1 cleaves Ng in its IQ domain upon activation by Ca ions. This IQ domain is essential for modulating calmodulin and CaMKII signaling toward LTP. Using SEC, western blotting, and IP‐MS, we show that N‐terminal Ng and high molecular weight forms of Ng can be also be found in CSF. These Ng forms may have physiologic relevance and be of importance for the understanding of pathologic processes in brain disorders and for the development of specific biomarker assays.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3358f0b74d00cff04dada3fbd1256a32Test
https://pubmed.ncbi.nlm.nih.gov/33249594Test

المؤلفون: Ido P. Kema, Yannick Vermeiren, Ellen A. A. Nollen, Peter Paul De Deyn, Freek J. H. Sorgdrager, Claude van der Ley, Martijn van Faassen

المساهمون: Molecular Neuroscience and Ageing Research (MOLAR), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM)

المصدر: Journal of Neurochemistry 151 (2019) 5
Journal of Neurochemistry, 151(5), 656-668. Blackwell Publishing Ltd
Journal of Neurochemistry
Journal of neurochemistry
Journal of Neurochemistry, 151(5), 656-668

مصطلحات موضوعية: 0301 basic medicine, Male, medicine.medical_specialty, Aging, Kynurenine pathway, Parkinson's disease, Excitotoxicity, medicine.disease_cause, Biochemistry, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Cerebrospinal fluid, Kynurenic acid, Alzheimer Disease, kynurenic acid, Internal medicine, Medicine, Humans, Biology, Aged, business.industry, Clinical Studies, Biomakers & Imaging, Neurodegeneration, neurodegeneration, Parkinson Disease, Middle Aged, medicine.disease, kynurenine, Chemistry, 030104 developmental biology, Endocrinology, chemistry, ageing, Parkinson’s disease, Original Article, Female, Human medicine, ORIGINAL ARTICLES, business, Alzheimer’s disease, 030217 neurology & neurosurgery, Kynurenine, Quinolinic acid

الوصف: The kynurenine (Kyn) pathway, which regulates neuroinflammation and N‐methyl‐d‐aspartate receptor activation, is implicated in Parkinson’s disease (PD) and Alzheimer’s disease (AD). Age‐related changes in Kyn metabolism and altered cerebral Kyn uptake along large neutral amino acid transporters, could contribute to these diseases. To gain further insight into the role and prognostic potential of the Kyn pathway in PD and AD, we investigated systemic and cerebral Kyn metabolite production and estimations of their transporter‐mediated uptake in the brain. Kyn metabolites and large neutral amino acids were retrospectively measured in serum and cerebrospinal fluid (CSF) of clinically well‐characterized PD patients (n = 33), AD patients (n = 33), and age‐matched controls (n = 39) using solid‐phase extraction‐liquid chromatographic‐tandem mass spectrometry. Aging was disease independently associated with increased Kyn, kynurenic acid and quinolinic acid in serum and CSF. Concentrations of kynurenic acid were reduced in CSF of PD and AD patients (p = 0.001; p = 0.002) but estimations of Kyn brain uptake did not differ between diseased and controls. Furthermore, serum Kyn and quinolinic acid levels strongly correlated with their respective content in CSF and Kyn in serum negatively correlated with AD disease severity (p = 0.002). Kyn metabolites accumulated with aging in serum and CSF similarly in PD patients, AD patients, and control subjects. In contrast, kynurenic acid was strongly reduced in CSF of PD and AD patients. Differential transporter‐mediated Kyn uptake is unlikely to majorly contribute to these cerebral Kyn pathway disturbances. We hypothesize that the combination of age‐ and disease‐specific changes in cerebral Kyn pathway activity could contribute to reduced neurogenesis and increased excitotoxicity in neurodegenerative disease.
To study the role and diagnostic potential of the kynurenine (Kyn) pathway in age‐related neurodegenerative disease, time‐linked serum, and cerebrospinal fluid (CSF) samples from Alzheimer’s disease (AD) patients, Parkinson’s disease (PD) patients and age‐matched cognitively healthy controls were retrospectively selected. Kyn metabolites and large neutral amino acids (LNAAs), which compete with Kyn metabolites to cross the blood–brain barrier, were analyzed by mass spectrometry. Age‐related increases of several Kyn metabolites were similar in controls, AD, and PD. Concentrations of kynurenic acid (KA), which plays a role in glutamate toxicity and neuronal development, were strongly reduced in CSF of PD and AD patients.

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الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::069147d6e5d34efbad985448ca4b5613Test
https://research.wur.nl/en/publications/age-and-disease-specific-changes-of-the-kynurenine-pathway-in-parTest