| 1. |
- Moen, Vibeke, et al.
(author)
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Feto-maternal osmotic balance at term. A prospective observational study
- 2018
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In: Journal of Perinatal Medicine. - : WALTER DE GRUYTER GMBH. - 0300-5577 .- 1619-3997. ; 46:2, s. 183-189
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Journal article (peer-reviewed)abstract
- Objective: We performed the present study to investigate the feto-maternal osmotic relationship at term with the hypothesis that, in contrast to the literature, maternal plasma osmolality is lower than fetal levels. In a previous study, we found that maternal plasma sodium at delivery was consistently lower than the sodium in the umbilical artery. Our aim was to corroborate these results with analysis of osmolality. Methods: Blood was sampled from 30 women immediately before cesarean section and from the umbilical artery and vein before cord clamping and osmolality, sodium and albumin were analyzed. Results: Maternal osmolality was (mean; 95% confidence interval) 287.0 (285.8-288.2) mOsmkg/kg, arterial cord osmolality was 289.4 (287.9-291.0) mOsm/kg and venous cord osmolality was 287.3 (286.0-288.5) mOsm/kg. The paired difference between maternal and umbilical arterial osmolality was mean (SD) -2.4 (3.3) mOsm/kg (P amp;lt; 0.001), between maternal and umbilical vein -0.3 (3.0) mOsm/kg (P = 0.63) and between umbilical artery and vein -2.1 (2.8) mOsm/kg (P amp;lt; 0.001). Conclusion: Maternal osmolality was significantly lower than arterial cord osmolality confirming our previous results. The feto-maternal osmotic gradient favors water transport from the mother to the fetus and may increase the fetal risk of water intoxication when the mother ingests or is administered large volumes of electrolyte free solutions.
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| 2. |
- Carlsson, Hanna, et al.
(author)
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Subclinical Lyme borreliosis is common in south-eastern Sweden and may be distinguished from Lyme neuroborreliosis by sex, age and specific immune marker patterns
- 2018
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In: Ticks and Tick-borne Diseases. - : ELSEVIER GMBH, URBAN & FISCHER VERLAG. - 1877-959X .- 1877-9603. ; 9:3, s. 742-748
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Journal article (peer-reviewed)abstract
- Background: Determinants of a subclinical course of Lyme borreliosis (LB) remain largely unknown. The aim of this study was to assess the extent, sex and age profiles of subclinical Borrelia seroconversion in a LB endemic area in Sweden and to map blood cellular Borrelia-specific immune marker patterns in individuals with a previous subclinical LB course compared with patients previously diagnosed with Lyme neuroborreliosis (LNB). Methods: A large group of 1113 healthy blood donors was screened for multiple IgG anti-Borrelia antibodies and asked to complete a health inquiry regarding previous LB. A group of subjects with anti-Borrelia-specific IgG antibodies but no previous history of LB (subclinical LB, n = 60) was identified together with 22 cases of previous LNB. Whole Borrelia spirochetes, strains B. afzelii ACA1 and B. garinii Ip90, were used for ex vivo whole blood stimulations, whereas outer surface protein enriched fractions of the same strains were used for stimulation of peripheral blood mononuclear cells (PBMCs). An extensive panel of immune markers was analysed in the supernatants after stimulation using multiplex bead arrays, and Borrelia-specific secretion was determined by subtracting the spontaneous secretion. Results: A total of 125/1113 blood donors reported previous clinical LB. In contrast, 66 donors denied previous LB but showed multiple IgG anti-Borrelia antibodies; these were defined as subclinical subjects, of whom 60 were available for further studies. The subclinical subjects consisted of significantly more men and had a younger age compared with the LNB patients (p amp;lt;= 0.01). Discriminant analysis revealed a distinct pattern of sex, age and PBMC B. garinii-specific levels of IL-10, IL-17A and CCL20 discriminating subclinical subjects from LNB patients. Conclusions: This study confirms that subclinical Borrelia seroconversion is common in south-eastern Sweden. The findings further suggest that male sex, younger age together with B. gariniii induced levels of IL-10, IL-17A and CCL20 may be associated with a subclinical course.
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| 3. |
- Domert, Jakob, 1986-
(author)
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Neuron-to-neuron propagation of neurodegenerative proteins; relation to degradative systems
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Alzheimer’s disease (AD) and Parkinson’s disease (PD) are defined by neurodegeneration and accumulations of misfolded proteins that spread through the brain in a well characterized manner. In AD these accumulations consist mainly of β-amyloid (Aβ) and tau, while in PD, α-synuclein (α-syn) make up the characteristic lewy pathology. The general aim of this thesis was to investigate mechanisms associated with neurotoxic peptide activity by Aβ, tau and α-syn in relation to cellular degradation and transfer with a cell-to-cell transfer model system. We found that intercellular transfer of oligomeric Aβ occurs independently of isoform. However, the amount of transfer correlates with each isoforms ability to resist degradation or cellular clearance. The Aβ1-42 isoform showed particular resistance to clearance, which resulted in higher levels of cell-to-cell transfer of the isoform and lysosomal stress caused by accumulation. As Aβ accumulations can inhibit the proteasomal degradation we investigated how reduced proteasomal degradation affected neuron-like cells. We found increased levels of phosphorylated tau protein, disturbed microtubule stability and impaired neuritic transport after reduced proteasomal activity. These changes was partly linked to c-Jun and ERK 1/2 kinase activity. We could also show that α-syn transferred from cell-to-cell in our model system, with a higher degree of transfer for the larger oligomer and fibrillar species. Similar to Aβ, α-syn mainly colocalized with lysosomes, before and after transfer. Lastly, we have developed our cell-to-cell transfer system into a model suitable for high throughput screening (HTS). The type of cells have been upgraded from SH-SY5Y cells to induced pluripotent stem cells (iPSCs), with a differentiation profile more similar to mature neurons. The next step will be screening a small molecular library for substances with inhibitory effect on cell-to-cell transfer of Aβ peptides. The importance of the degradative systems in maintaining protein homeostasis and prevent toxic accumulations in general is well known. Our findings shows the importance of these systems for neurodegenerative diseases and also highlight the link between degradation and cell-to-cell transfer. To restore or enhance the degradative systems would be an interesting avenue to treat neurodegenerative diseases. Another way would be to inhibit the transfer of misfolded protein aggregates. By using the HTS model we developed, a candidate substance with good inhibitory effect on transfer can hopefully be found.
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| 4. |
- Lundgren, Jolanta L, et al.
(author)
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ADAM10 and BACE1 are localized to synaptic vesicles.
- 2015
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In: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 135:3, s. 606-615
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Journal article (peer-reviewed)abstract
- Synaptic degeneration and accumulation of the neurotoxic amyloid β-peptide (Aβ) in the brain are hallmarks of Alzheimer disease. Aβ is produced by sequential cleavage of its precursor protein, APP, by the β-secretase BACE1 and γ-secretase. However, Aβ generation is precluded if APP is cleaved by the α-secretase ADAM10 instead of BACE1. We have previously shown that Aβ can be produced locally at the synapse. To study the synaptic localization of the APP processing enzymes we used western blotting to demonstrate that, compared to total brain homogenate, ADAM10 and BACE1 were greatly enriched in synaptic vesicles isolated from rat brain using controlled-pore glass chromatography, whereas Presenilin1 was the only enriched component of the γ-secretase complex. Moreover, we detected ADAM10 activity in synaptic vesicles and enrichment of the intermediate APP-C-terminal fractions (APP-CTFs). We confirmed the western blotting findings using in situ proximity ligation assay to demonstrate close proximity of ADAM10 and BACE1 with the synaptic vesicle marker synaptophysin in intact mouse primary hippocampal neurons. In contrast, only sparse co-localization of active γ-secretase and synaptophysin was detected. These results indicate that the first step of APP processing occurs in synaptic vesicles whereas the final step is more likely to take place elsewhere. This article is protected by copyright. All rights reserved.
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| 5. |
- Martinsson, Isak, et al.
(author)
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APP depletion alters selective pre- and post-synaptic proteins
- 2019
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In: Molecular and Cellular Neuroscience. - : Elsevier BV. - 1044-7431 .- 1095-9327. ; 95, s. 86-95
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Journal article (peer-reviewed)abstract
- The normal role of Alzheimer's disease (AD)-linked amyloid precursor protein (APP) in the brain remains incompletely understood. Previous studies have reported that lack of APP has detrimental effects on spines and electrophysiological parameters. APP has been described to be important in synaptic pruning during development. The effect of APP knockout on mature synapses is complicated by this role in development. We previously reported on differential changes in synaptic proteins and receptors in APP mutant AD transgenic compared to wild-type neurons, which revealed selective decreases in levels of pre- and post-synaptic proteins, including of surface glutamate receptors. In the present study, we undertook a similar analysis of synaptic composition but now in APP knockout compared to wild-type mouse neurons. Here we demonstrate alterations in levels of selective pre- and post-synaptic proteins and receptors in APP knockout compared to wild-type mouse primary neurons in culture and brains of mice in youth and adulthood. Remarkably, we demonstrate selective increases in levels of synaptic proteins, such as GluA1, in neurons with APP knockout and with RNAi knockdown, which tended to be opposite to the reductions seen in AD transgenic APP mutant compared to wild-type neurons. These data reinforce that APP is important for the normal composition of synapses.
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| 6. |
- Nilsson, Per, et al.
(author)
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Loss of neprilysin alters protein expression in the brain of Alzheimer's disease model mice
- 2015
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In: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 15:19, s. 3349-3355
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is a neurodegenerative disease displaying extracellular plaques formed by the neurotoxic amyloid -peptide (A), and intracellular neurofibrillary tangles consisting of protein tau. However, how these pathologies relate to the massive neuronal death that occurs in AD brains remain elusive. Neprilysin is the major A-degrading enzyme and a lack thereof increases A levels in the brain twofold. To identify altered protein expression levels induced by increased A levels, we performed a proteomic analysis of the brain of the AD mouse model APPsw and compared it to that of APPsw mice lacking neprilysin. To this end we established an LC-MS/MS method to analyze brain homogenate, using an O-18-labeled internal standard to accurately quantify the protein levels. To distinguish between alterations in protein levels caused by increased A levels and those induced by neprilysin deficiency independently of A, the brain proteome of neprilysin deficient APPsw mice was also compared to that of neprilysin deficient mice. By this approach we identified approximately 600 proteins and the levels of 300 of these were quantified. Pathway analysis showed that many of the proteins with altered expression were involved in neurological disorders, and that tau, presenilin and APP were key regulators in the identified networks. The data have been deposited to the ProteomeXchange Consortium with identifiers PXD000968 and PXD001786 ( and (). Interestingly, the levels of several proteins, including some not previously reported to be linked to AD, were associated with increased A levels.
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| 7. |
- Rising, Anna, et al.
(author)
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Systemic AA amyloidosis in the red fox (Vulpes vulpes)
- 2017
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In: Protein Science. - : WILEY. - 0961-8368 .- 1469-896X. ; 26:11, s. 2312-2318
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Journal article (peer-reviewed)abstract
- Amyloid A (AA) amyloidosis occurs spontaneously in many mammals and birds, but the prevalence varies considerably among different species, and even among subgroups of the same species. The Blue fox and the Gray fox seem to be resistant to the development of AA amyloidosis, while Island foxes have a high prevalence of the disease. Herein, we report on the identification of AA amyloidosis in the Red fox (Vulpes vulpes). Edman degradation and tandem MS analysis of proteolyzed amyloid protein revealed that the amyloid partly was composed of full-length SAA. Its amino acid sequence was determined and found to consist of 111 amino acid residues. Based on inter-species sequence comparisons we found four residue exchanges (Ser31, Lys63, Leu71, Lys72) between the Red and Blue fox SAAs. Lys63 seems unique to the Red fox SAA. We found no obvious explanation to how these exchanges might correlate with the reported differences in SAA amyloidogenicity. Furthermore, in contrast to fibrils from many other mammalian species, the isolated amyloid fibrils from Red fox did not seed AA amyloidosis in a mouse model.
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| 8. |
- Schedin-Weiss, Sophia, et al.
(author)
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Super-resolution microscopy reveals gamma-secretase at both sides of the neuronal synapse
- 2016
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In: Acta neuropathologica communications. - : BioMed Central. - 2051-5960. ; 4
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Journal article (peer-reviewed)abstract
- The transmembrane protein assembly gamma-secretase is a key protease in regulated intramembrane processing (RIP) of around 100 type-1 transmembrane proteins. Importantly, it has a pathological role in Alzheimer disease (AD) as it generates the neurotoxic amyloid beta-peptide from the amyloid precursor protein (APP). Studies on gamma-secretase location are therefore crucial both from a biological and a therapeutic perspective. Despite several years of efforts in many laboratories, it is not clear where in the neuron gamma-secretase exerts it's activities. Technical challenges include the fact that the active enzyme contains four protein components and that most subcellular compartments cannot be spatially resolved by traditional light microscopy. Here, we have used a powerful combination of the two nanoscopy techniques STORM and STED microscopy to visualize the location of gamma-secretase in neurons using an active-site specific probe, with a focus on the synapse. We show that gamma-secretase is present in both the pre-and postsynaptic compartments. We further show that the enzyme is enriched very close to the synaptic cleft in the postsynaptic membrane, as well as to NMDA receptors, demonstrating that gamma-secretase is present in the postsynaptic plasma membrane. Importantly, the expression of gamma-secretase increased in the pre-and postsynaptic compartments with the size of the synapse, suggesting a correlation between gamma-secretase activity and synapse maturation. Thus, our data shows the synaptic location with high precision in three dimensions and settles the long-lasting debate on the synaptic location of gamma-secretase.
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| 9. |
- Wennmalm, Stefan, et al.
(author)
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Highly Sensitive FRET-FCS Detects Amyloid beta-Peptide Oligomers in Solution at Physiological Concentrations
- 2015
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In: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 87:23, s. 11700-11705
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Journal article (peer-reviewed)abstract
- Oligomers formed by the amyloid beta-peptide (A beta) are pathogens in Alzheimers disease. Increased knowledge on the oligomerization process is crucial for understanding the disease and for finding treatments. Ideally, A beta oligomerization should be studied in solution and at physiologically relevant concentrations, but most popular techniques of today are not capable of such analyses. We demonstrate here that the combination of FOrster Resonance Energy Transfer and Fluorescence Correlation Spectroscopy (FRET-FCS) has a unique ability to detect small subpopulations of FRET-active molecules and oligomers. FRET-FCS could readily detect a FRET-active oligonucleotide present at levels as low as 0.5% compared to FRET-inactive dye molecules. In contrast, three established fluorescence fluctuation techniques (FCS, FCCS, and PCH) required fractions between 7 and 11%. When applied to the analysis of A beta, FRET-FCS detected oligomers consisting of less than 10 A beta molecules, which coexisted with the monomers at fractions as low as 2 +/- 2%. Thus, we demonstrate for the first time direct detection of small fractions of A beta oligomers in solution at physiological concentrations. This ability of FRET-FCS could be an indispensable tool for studying biological oligomerization processes, in general, and for finding therapeutically useful oligomerization inhibitors.
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| 10. |
- Yu, Yang, et al.
(author)
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Neuronal A beta 42 is enriched in small vesicles at the presynaptic side of synapses
- 2018
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In: Life Science Alliance. - : LIFE SCIENCE ALLIANCE LLC. - 2575-1077. ; 1:3
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Journal article (peer-reviewed)abstract
- The amyloid beta-peptide (A beta) is a physiological ubiquitously expressed peptide suggested to be involved in synaptic function, long-term potentiation, and memory function. The 42 amino acid-long variant (A beta 42) forms neurotoxic oligomers and amyloid plaques and plays a key role in the loss of synapses and other pathogenic events of Alzheimer disease. Still, the exact localization of A beta 42 in neurons and at synapses has not been reported. Here, we used super-resolution microscopy and show that A beta 42 was present in small vesicles in presynaptic compartments, but not in postsynaptic compartments, in the neurites of hippocampal neurons. Some of these vesicles appeared to lack synaptophysin, indicating that they differ from the synaptic vesicles responsible for neurotransmitter release. The A beta 42-containing vesicles existed in presynapses connected to stubby spines and mushroom spines, and were also present in immature presynapses. These vesicleswere scarce inother parts of the neurites, where A beta 42 was instead present in large, around 200-600 nm, vesicular structures. Three-dimensional super-resolution microscopy confirmed that A beta 42 was present in the presynapse and absent in the postsynapse.
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