| 1. |
- Baey, Charlotte, et al.
(author)
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A model to account for data dependency when estimating floral cover in different land use types over a season
- 2017
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In: Environmental and Ecological Statistics. - : Springer Science and Business Media LLC. - 1352-8505 .- 1573-3009. ; 24:4, s. 505-527
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Journal article (peer-reviewed)abstract
- We propose a model to consider data dependencies and assess spatial and temporal variability in land use specific floral coverage across landscapes. Data dependence arising from repeated measurements across the flowering season is taken into account using hierarchical Archimedean copulas, where the correlation is assumed to be stronger within seasonal periods than between periods. For each seasonal period, a bounded probability distribution is assigned to capture spatial variability in floral cover. The model uses a Bayesian approach and can assess land-use-specific floral covers by integrating experts judgments and field data. The model is applied to assess floral covers in four land use types in southern Sweden, where seasonal variability is captured by dividing the season into two periods according to winter oilseed rape flowering. Floral cover is updated using Markov Chain Monte Carlo sampling based on data from 16 landscapes and 2 years, with repeated measures available from each of the two seasonal periods. Our results indicate that considering data dependence improved the estimation of floral cover based on data observed during a season. Different copula families specifying multivariate probability distributions were tested, and no family had a consistently higher performance in the four tested land use types. Uncertainty in both mode and variability of floral cover was higher when data dependence were accounted for. Posterior modes of floral covers in semi-natural grassland were higher than in field edges, but both expert’s best guesses were higher than these estimates. This confirms previous findings in expert elicitation processes that experts may fail to discriminate extreme values on a bounded range. Floral cover in flower strips were estimated to be smaller/higher than semi-natural grasslands early/late in the season. The mode of floral cover in oil seed rape was estimated to be close to 100%, and higher than estimates provided by expert judgment. Floral covers for different land use classes are key parameters when quantifying floral resources at a landscape level whose assessments rely on both expert judgment and field measurements.
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| 2. |
- Baey, Charlotte, et al.
(author)
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Calibration of a bumble bee foraging model using Approximate Bayesian Computation
- 2023
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In: Ecological Modelling. - : Elsevier BV. - 0304-3800. ; 477
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Journal article (peer-reviewed)abstract
- 1. Challenging calibration of complex models can be approached by using prior knowledge on the parameters. However, the natural choice of Bayesian inference can be computationally heavy when relying on Markov Chain Monte Carlo (MCMC) sampling. When the likelihood of the data is intractable, alternative Bayesian methods have been proposed. Approximate Bayesian Computation (ABC) only requires sampling from the data generative model, but may be problematic when the dimension of the data is high. 2. We studied alternative strategies to handle high dimensional data in ABC applied to the calibration of a spatially explicit foraging model for Bombus terrestris. The first step consisted in building a set of summary statistics carrying enough biological meaning, i.e. as much as the original data, and then applying ABC on this set. Two ABC strategies, the use of regression adjustment leading to the production of ABC posterior samples, and the use of machine learning approaches to approximate ABC posterior quantiles, were compared with respect to coverage of model estimates and true parameter values. The comparison was made on simulated data as well as on data from two field studies. 3. Results from simulated data showed that some model parameters were easier to calibrate than others. Approaches based on random forests in general performed better on simulated data. They also performed well on field data, even though the posterior predictive distribution exhibited a higher variance. Nonlinear regression adjustment performed better than linear ones, and the classical ABC rejection algorithm performed badly. 4. ABC is an interesting and appealing approach for the calibration of complex models in biology, such as spatially explicit foraging models. However, while ABC methods are easy to implement, they often require considerable tuning.
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| 3. |
- Fagerqvist, Therese, et al.
(author)
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Monoclonal antibodies selective for α-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α-synuclein transgenic mice with the disease-causing A30P mutation
- 2013
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In: Journal of Neurochemistry. - : Wiley-Blackwell. - 0022-3042 .- 1471-4159. ; 126:1, s. 131-144
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Journal article (peer-reviewed)abstract
- Inclusions of intraneuronal alpha-synuclein (-synuclein) can be detected in brains of patients with Parkinson's disease and dementia with Lewy bodies. The aggregation of -synuclein is a central feature of the disease pathogenesis. Among the different -synuclein species, large oligomers/protofibrils have particular neurotoxic properties and should therefore be suitable as both therapeutic and diagnostic targets. Two monoclonal antibodies, mAb38F and mAb38E2, with high affinity and strong selectivity for large -synuclein oligomers were generated. These antibodies, which do not bind amyloid-beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in -synuclein transgenic mice than linear epitope antibodies. An oligomer-selective sandwich ELISA, based on mAb38F, was set up to analyze brain extracts of the transgenic mice. The overall levels of -synuclein oligomers/protofibrils were found to increase with age in these mice, although the levels displayed a large interindividual variation. Upon subcellular fractionation, higher levels of -synuclein oligomers/protofibrils could be detected in the endoplasmic reticulum around the age when behavioral disturbances develop. In summary, our novel oligomer-selective -synuclein antibodies recognize relevant pathology and should be important tools to further explore the pathogenic mechanisms in Lewy body disorders. Moreover, they could be potential candidates both for immunotherapy and as reagents in an assay to assess a potential disease biomarker.
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| 4. |
- Fagerqvist, Therese, et al.
(author)
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Off-pathway alpha-synuclein oligomers seem to alter alpha-synuclein turnover in a cell model but lack seeding capability in vivo
- 2013
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In: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 20:4, s. 233-244
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Journal article (peer-reviewed)abstract
- Aggregated α-synuclein is the major component of Lewy bodies, protein inclusions observed in the brain in neurodegenerative disorders such as Parkinson’s disease and dementia with Lewy bodies. Experimental evidence indicates that α-synuclein potentially can be transferred between cells and act as a seed to accelerate the aggregation process. Here, we investigated in vitro and in vivo seeding effects of α-synuclein oligomers induced by the reactive aldehyde 4-oxo-2-nonenal (ONE). As measured by a Thioflavin-T based fibrillization assay, there was an earlier onset of aggregation when α-synuclein oligomers were added to monomeric α-synuclein. In contrast, exogenously added α-synuclein oligomers did not induce aggregation in a cell model. However, cells overexpressing α-synuclein that were treated with the oligomers displayed reduced α-synuclein levels, indicating that internalized oligomers either decreased the expression or accelerated the degradation of transfected α-synuclein. Also in vivo there were no clear seeding effects, as intracerebral injections of α-synuclein oligomers into the neocortex of α-synuclein transgenic mice did not induce formation of Proteinase K resistant α-synuclein pathology. Taken together, we could observe a seeding effect of the ONE-induced α-synuclein oligomers in a fibrillization assay, but neither in a cell nor in a mouse model.
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| 5. |
- Fagerqvist, Therese, et al.
(author)
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Off-pathway α-synuclein oligomers seem to alter α-synuclein turnover in a cell model but lack seeding capability in vivo
- 2013
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In: Amyloid. - : Informa Healthcare. - 1350-6129 .- 1744-2818. ; 20:4, s. 233-244
-
Journal article (peer-reviewed)abstract
- Aggregated alpha-synuclein is the major component of Lewy bodies, protein inclusions observed in the brain in neurodegenerative disorders such as Parkinson's disease and dementia with Lewy bodies. Experimental evidence indicates that alpha-synuclein potentially can be transferred between cells and act as a seed to accelerate the aggregation process. Here, we investigated in vitro and in vivo seeding effects of alpha-synuclein oligomers induced by the reactive aldehyde 4-oxo-2-nonenal (ONE). As measured by a Thioflavin-T based fibrillization assay, there was an earlier onset of aggregation when alpha-synuclein oligomers were added to monomeric alpha-synuclein. In contrast, exogenously added alpha-synuclein oligomers did not induce aggregation in a cell model. However, cells overexpressing alpha-synuclein that were treated with the oligomers displayed reduced alpha-synuclein levels, indicating that internalized oligomers either decreased the expression or accelerated the degradation of transfected alpha-synuclein. Also in vivo there were no clear seeding effects, as intracerebral injections of alpha-synuclein oligomers into the neocortex of alpha-synuclein transgenic mice did not induce formation of proteinase K resistant alpha-synuclein pathology. Taken together, we could observe a seeding effect of the ONE-induced alpha-synuclein oligomers in a fibrillization assay, but neither in a cell nor in a mouse model.
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| 6. |
- Gkanatsiou, Eleni, et al.
(author)
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Characterization of monomeric and soluble aggregated Aβ in Down's syndrome and Alzheimer's disease brains.
- 2021
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In: Neuroscience letters. - : Elsevier BV. - 1872-7972 .- 0304-3940. ; 754
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Journal article (peer-reviewed)abstract
- The major characteristics of Alzheimer's disease (AD) are amyloid plaques, consisting of aggregated beta amyloid (Aβ) peptides, together with tau pathology (tangles, neuropil treads and dystrophic neurites surrounding the plaques), in the brain. Down's syndrome (DS) individuals are at increased risk to develop AD-type pathology; most DS individuals have developed substantial pathology already at the age of 40. DS individuals have an extra copy of chromosome 21, harbouring the amyloid precursor protein gene (APP). Our aim was to investigate the Aβ peptide pattern in DS and AD brains to investigate differences in their amyloid deposition and aggregation, respectively. Cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (water soluble) and formic acid (water insoluble) fractions. Immunoprecipitation (IP) was performed using a variety of antibodies targeting different Aβ species including oligomeric Aβ. Mass spectrometry was then used to evaluate the presence of Aβ species in the different patient groups. A large number of Aβ peptides were identified including Aβ1-X, 2-X, 3-X, 4-X, 5-X, 11-X, and Aβ peptides extended N terminally of the BACE1 cleavage site and ending at amino 15 in the Aβ sequence APP/Aβ(-X to 15), as well as peptides post-translationally modified by pyroglutamate formation. Most Aβ peptides had higher abundance in AD and DS compared to controls, except the APP/Aβ(-X to 15) peptides which were most abundant in DS followed by controls and AD. Furthermore, the abundancies of AβX-40 and AβX-34 were increased in DS compared with AD. Aβ1-40, Aβ1-42, and Aβ4-42 were identified as the main constitutes of protofibrils (IP'd using mAb158) and higher relative Aβ1-42 signals were obtained compared with samples IP'd with 6E10+4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at amino acid 42. All Aβ peptides found in AD were also present in DS indicating similar pathways of Aβ peptide production, degradation and accumulation, except for APP/Aβ(-X to 15). Likewise, the Aβ peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility that treatment with clinical benefit in sporadic AD might also be beneficial for subjects with DS.
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| 7. |
- Häussler, Johanna, et al.
(author)
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Pollinator population size and pollination ecosystem service responses to enhancing floral and nesting resources
- 2017
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In: Ecology and Evolution. - : Wiley. - 2045-7758. ; 7:6, s. 1898-1908
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Journal article (peer-reviewed)abstract
- Modeling pollination ecosystem services requires a spatially explicit, process-based approach because they depend on both the behavioral responses of pollinators to the amount and spatial arrangement of habitat and on the within- and between-season dynamics of pollinator populations in response to land use. We describe a novel pollinator model predicting flower visitation rates by wild central-place foragers (e.g., nesting bees) in spatially explicit landscapes. The model goes beyond existing approaches by: (1) integrating preferential use of more rewarding floral and nesting resources; (2) considering population growth over time; (3) allowing different dispersal distances for workers and reproductives; (4) providing visitation rates for use in crop pollination models. We use the model to estimate the effect of establishing grassy field margins offering nesting resources and a low quantity of flower resources, and/or late-flowering flower strips offering no nesting resources but abundant flowers, on bumble bee populations and visitation rates to flowers in landscapes that differ in amounts of linear seminatural habitats and early mass-flowering crops. Flower strips were three times more effective in increasing pollinator populations and visitation rates than field margins, and this effect increased over time. Late-blooming flower strips increased early-season visitation rates, but decreased visitation rates in other late-season flowers. Increases in population size over time in response to flower strips and amounts of linear seminatural habitats reduced this apparent competition for pollinators. Our spatially explicit, process-based model generates emergent patterns reflecting empirical observations, such that adding flower resources may have contrasting short- and long-term effects due to apparent competition for pollinators and pollinator population size increase. It allows exploring these effects and comparing effect sizes in ways not possible with other existing models. Future applications include species comparisons, analysis of the sensitivity of predictions to life-history traits, as well as large-scale management intervention and policy assessment.
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| 8. |
- Johannesson, Malin, et al.
(author)
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Elevated soluble amyloid beta protofibrils in Down syndrome and Alzheimer's disease
- 2021
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In: Molecular and Cellular Neuroscience. - : Elsevier. - 1044-7431 .- 1095-9327. ; 114
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Journal article (peer-reviewed)abstract
- Down syndrome (DS) is caused by trisomy of chromosome 21, which leads to a propensity to develop amyloid beta (A beta) brain pathology in early adulthood followed later by cognitive and behavioral deterioration. Characterization of the A beta pathology is important to better understand the clinical deterioration of DS individuals and to identify interventive strategies. Brain samples from people with DS and Alzheimer's disease (AD), as well as nondemented controls (NDC), were analyzed with respect to different A beta species. Immunohistochemical staining using antibodies towards A beta was also performed. Elevated levels of soluble A beta protofibrils and insoluble A beta x-40 and A beta x-42 in formic acid brain extracts, and elevated immunohistochemical staining of A beta deposits were demonstrated with the antibody BAN2401 (lecanemab) in DS and AD compared with NDC. These data and the promising data in a large phase 2 CE clinical trial with lecanemab suggest that lecanemab may have the potential to preserve cognitive capacity in DS. Lecanemab is currently in a phase 3 CE clinical trial.
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| 9. |
- Näsström, Thomas, et al.
(author)
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Antibodies against alpha-synuclein reduce oligomerization in living cells
- 2011
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:10, s. e27230-
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Journal article (peer-reviewed)abstract
- Recent research implicates soluble aggregated forms of α-synuclein as neurotoxic species with a central role in the pathogenesis of Parkinson’s disease and related disorders. The pathway by which α-synuclein aggregates is believed to follow a step-wise pattern, in which dimers and smaller oligomers are initially formed. Here, we used H4 neuroglioma cells expressing α-synuclein fused to hemi:GFP to study the effects of α-synuclein monoclonal antibodies on the early stages of aggregation, as quantified by Bimolecular Fluorescence Complementation assay. Widefield and confocal microscopy revealed that cells treated for 48 h with monoclonal antibodies internalized antibodies to various degrees. Oligomer-selective and C-terminal specific α-synuclein antibodies reduced the extent of α-synuclein dimerization/oligomerization, as indicated by decreased GFP fluorescence signal. Furthermore, ELISA measurements on lysates and conditioned media from antibody treated cells displayed lower α-synuclein levels compared to untreated cells, suggesting increased protein turnover. Taken together, our results propose that extracellular administration of monoclonal antibodies can modify or inhibit early steps in the aggregation process of α-synuclein, thus providing further support for passive immunization against diseases with α-synuclein pathology.
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| 10. |
- Sahlin, Charlotte, et al.
(author)
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Docosahexaenoic acid stimulates non-amyloidogenic APP processing resulting in reduced Aβ levels in cellular models of Alzheimer's disease
- 2007
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In: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 26:4, s. 882-889
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Journal article (peer-reviewed)abstract
- Epidemiological studies suggest that a high intake of polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), is associated with a reduced risk of Alzheimer's disease. Here, we examined the effects of DHA on amyloid precursor protein (APP) processing in cellular models of Alzheimer's disease by analysing levels of different APP fragments, including amyloid-β (Aβ). DHA administration stimulated non-amyloidogenic APP processing and reduced levels of Aβ, providing a mechanism for the reported beneficial effects of DHA in vivo. However, an increased level of APP intracellular domain was also observed, highlighting the need to increase our knowledge about the relevance of this fragment in Alzheimer's disease pathogenesis. In conclusion, our results suggest that the proposed protective role of DHA in Alzheimer's disease pathogenesis might be mediated by altered APP processing and Aβ production.
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| 11. |
- Sahlin, Charlotte, 1977-
(author)
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Pathogenic Mechanisms of the Arctic Alzheimer Mutation
- 2007
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Doctoral thesis (other academic/artistic)abstract
- Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by neurofibrillay tangles and deposition of amyloid-β (Aβ) peptides. Several mutations in the gene for amyloid precursor protein (APP) cause familial AD and affect APP processing leading to increased levels of Aβ42. However, the Arctic Alzheimer mutation (APP E693G) reduces Aβ levels. Instead, the increased tendency of Arctic Aβ peptides to form Aβ protofibrils is thought to contribute to the pathogenesis.In this thesis, the pathogenic mechanisms of the Arctic mutation were further investigated, specifically addressing if and how the mutation affects APP processing. Evidence of a shift towards β-secretase cleavage of Arctic APP was demonstrated. Arctic APP did not appear to be an inferior substrate for α-secretase, but the availability of Arctic APP for α-secretase cleavage was reduced, with diminished levels of cell surface APP in Arctic cells. Interestingly, administration of the fatty acid docosahexaenoic acid (DHA) stimulated α-secretase cleavage and partly reversed the effects of the Arctic mutation on APP processing.In contrast to previous findings, the Arctic mutation generated enhanced total Aβ levels suggesting increased Aβ production. Importantly, this thesis illustrates and explains why measures of both Arctic and wild type Aβ levels are highly dependent upon the Aβ assay used, with enzyme-linked immunosorbent assay (ELISA) and Western blot generating different results. It was shown that these differences were due to inefficient detection of Aβ oligomers by ELISA leading to an underestimation of total Aβ levels.In conclusion, the Arctic APP mutation leads to AD by multiple mechanisms. It facilitates protofibril formation, but it also alters trafficking and processing of APP which leads to increased steady state levels of total Aβ, in particular at intracellular locations. Importantly, these studies highlight mechanisms, other than enhanced production of Aβ peptide monomers, which could be implicated in sporadic AD.
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| 12. |
- Sahlin, Charlotte, et al.
(author)
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The Arctic Alzheimer mutation favors intracellular amyloid-beta production by making amyloid precursor protein less available to alpha-secretase
- 2007
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In: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 101:3, s. 854-862
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Journal article (peer-reviewed)abstract
- Mutations within the amyloid-β (Aβ) domain of the amyloid precursor protein (APP) typically generate hemorrhagic strokes and vascular amyloid angiopathy. In contrast, the Arctic mutation (APP E693G) results in Alzheimer's disease. Little is known about the pathologic mechanisms that result from the Arctic mutation, although increased formation of Aβ protofibrils in vitro and intraneuronal Aβ aggregates in vivo suggest that early steps in the amyloidogenic pathway are facilitated. Here we show that the Arctic mutation favors proamyloidogenic APP processing by increased β-secretase cleavage, as demonstrated by altered levels of N- and C-terminal APP fragments. Although the Arctic mutation is located close to the α-secretase site, APP harboring the Arctic mutation is not an inferior substrate to a disintegrin and metalloprotease-10, a major α-secretase. Instead, the localization of Arctic APP is altered, with reduced levels at the cell surface making Arctic APP less available for α-secretase cleavage. As a result, the extent and subcellular location of Aβ formation is changed, as revealed by increased Aβ levels, especially at intracellular locations. Our findings suggest that the unique clinical symptomatology and neuropathology associated with the Arctic mutation, but not with other intra-Aβ mutations, could relate to altered APP processing with increased steady-state levels of Arctic Aβ, particularly at intracellular locations.
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| 13. |
- Tucker, Stina, et al.
(author)
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The Murine Version of BAN2401 (mAb158) Selectively Reduces Amyloid-beta Protofibrils in Brain and Cerebrospinal Fluid of tg-ArcSwe Mice
- 2015
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 43:2, s. 575-588
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Journal article (peer-reviewed)abstract
- Amyloid-beta (A beta) immunotherapy for Alzheimer's disease (AD) has good preclinical support from transgenic mouse models and clinical data suggesting that a long-term treatment effect is possible. Soluble A beta protofibrils have been shown to exhibit neurotoxicity in vitro and in vivo, and constitute an attractive target for immunotherapy. Here, we demonstrate that the humanized antibody BAN2401 and its murine version mAb158 exhibit a strong binding preference for A beta protofibrils over A beta monomers. Further, we confirm the presence of the target by showing that both antibodies efficiently immunoprecipitate soluble A beta aggregates in human AD brain extracts. mAb158 reached the brain and reduced the brain protofibril levels by 42% in an exposure-dependent manner both after long-term and short-term treatment in tg-ArcSwe mice. Notably, a 53% reduction of protofibrils/oligomers in cerebrospinal fluid (CSF) that correlated with reduced brain protofibril levels was observed after long-term treatment, suggesting that CSF protofibrils/oligomers could be used as a potential biomarker. No change in native monomeric A beta(42) could be observed in brain TBS extracts after mAb158-treatment in tg-ArcSwe mice. By confirming the specific ability of mAb158 to selectively bind and reduce soluble A beta protofibrils, with minimal binding to A beta monomers, we provide further support in favor of its position as an attractive new candidate for AD immunotherapy. BAN2401 has undergone full phase 1 development, and available data indicate a favorable safety profile in AD patients.
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| 14. |
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| 15. |
- Wassénius, Emmy, et al.
(author)
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Creative destruction in academia : a time to reimagine practices in alignment with sustainability values
- 2023
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In: Sustainability Science. - : Springer Nature. - 1862-4065 .- 1862-4057. ; 18:6, s. 2769-2775
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Journal article (peer-reviewed)abstract
- Academia has experienced acceleration and expansion in parallel with the Great Acceleration, which has shaped the Anthropocene. Among other pressures, the expectation to be internationally mobile conflicts with many values held by sustainability scholars and results in disillusionment. The changes in the academic system can be seen through the framework of the adaptive cycle, which can help us understand historical parallels and shape the system to better align with sustainability values in future. We hope this piece can contribute to the discussion of the next steps forward to reimagine academia.
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