| 1. |
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| 2. |
- Dunning, Christopher, et al.
(författare)
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Direct High Affinity Interaction between Aβ42 and GSK3α Stimulates Hyperphosphorylation of Tau. A New Molecular Link in Alzheimer's Disease?
- 2016
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 7:2, s. 161-170
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid β peptide (Aβ42) assemblies are considered central to the development of Alzheimer's disease, but the mechanism of this toxicity remains unresolved. We screened protein microarrays with on-pathway oligomeric Aβ42 to identify candidate proteins interacting with toxic Aβ42 species. Samples prepared from Alexa546-Aβ42 and Aβ42 monomers at 1:5 molar ratio were incubated with the array during a time window of the amyloid fibril formation reaction during which the maximum number of transient oligomers exist in the reaction flux. A specific interaction was detected between Aβ42 and glycogen synthase kinase 3α (GSK3α), a kinase previously implicated in the disease pathology. This interaction was validated with anti-GSK3α immunoprecipitation assays in neuronal cell lysates. Confocal microscopy studies further identified colocalization of Aβ42 and GSK3α in neurites of mature primary mouse neurons. A high binding affinity (KD = 1 nM) was measured between Alexa488-Aβ42 and GSK3α in solution using thermophoresis. An even lower apparent KD was estimated between GSK3α and dextran-immobilized Aβ42 in surface plasmon resonance experiments. Parallel experiments with GSK3β also identified colocalization and high affinity binding to this isoform. GSK3α-mediated hyperphosphorylation of the protein tau was found to be stimulated by Aβ42 in in vitro phosphorylation assays and identified a functional relationship between the proteins. We uncover a direct and functional molecular link between Aβ42 and GSK3α, which opens an important avenue toward understanding the mechanism of Aβ42-mediated neuronal toxicity in Alzheimer's disease.
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| 3. |
- Edgar, James R, et al.
(författare)
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ESCRTs regulate amyloid precursor protein sorting in multivesicular bodies and intracellular beta amyloid accumulation.
- 2015
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Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 128:14, s. 2520-2528
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Tidskriftsartikel (refereegranskat)abstract
- Intracellular beta amyloid (Aβ) accumulation is a key feature of early Alzheimer's disease (AD) and precedes the appearance of Aβ in extracellular plaques. Aβ is generated through proteolytic processing of amyloid precursor protein (APP), but the intracellular site of Aβ production is unclear. APP has been localized to multivesicular endosomes/bodies (MVBs) where sorting of APP onto ILVs could promote amyloidogenic processing or reduce Aβ production/accumulation by sorting APP and processing products to lysosomes for degradation. We show that APP localizes to the ILVs of a subset of MVBs that also traffic EGF receptor (EGFR), and is delivered to lysosomes for degradation. Depletion of the ESCRT components, Hrs or Tsg101, inhibited targeting of APP to ILVs and the subsequent delivery to lysosomes and lead to increased intracellular Aβ accumulation. This was accompanied by dramatically decreased Aβ secretion. Thus, the early ESCRT machinery has a dual role in limiting intracellular Aβ accumulation through targeting of APP and processing products to the lysosome for degradation and promoting Aβ secretion.
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| 4. |
- Engström, Katarina, 1956, et al.
(författare)
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Irradiation of myxoid/round cell liposarcoma induces volume reduction and lipoma-like morphology
- 2007
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 46:6, s. 838-845
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to investigate the clinical and morphological effects of radiotherapy in the treatment of myxoid/round cell liposarcoma (MLS/RCLS). Thirty-three primary and metastatic MLS/RCLS tumours in 15 patients were treated with radiation therapy. Twenty-seven of the 33 tumours were surgically removed after preoperative radiation (34-46 Gy) while six tumours were treated with radiotherapy alone (44-60 Gy). The pretreatment diagnosis was established in all 15 patients based on fine needle aspirates or histological findings. Tumour size was measured by CT or MRI before and after radiotherapy in 30 tumours. Thirteen tumours from 11 patients were genetically characterised before and/or after radiation therapy. Twenty-three of 30 irradiated tumours showed a median reduction in tumour volume of 52% and seven lesions a median progression of 36%. All 27 surgically removed tumours revealed histological features of radiation response. The most striking morphological changes were lipoma-like appearance, paucicellularity and hyalinisation. Twelve of 13 tumours analysed before and/or after radiation therapy showed the FUS-DDIT3 translocation. Radiation therapy of MLS/RCLS induces histopathologic accumulation of mature lipoma-like areas and tumour volume reduction that may facilitate resectability.
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| 5. |
- Engström, Katarina, 1956, et al.
(författare)
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The myxoid/round cell liposarcoma fusion oncogene FUS-DDIT3 and the normal DDIT3 induce a liposarcoma phenotype in transfected human fibrosarcoma cells.
- 2006
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Ingår i: The American journal of pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 168:5, s. 1642-53
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Tidskriftsartikel (refereegranskat)abstract
- Myxoid/round cell liposarcoma (MLS/RCLS) is the most common subtype of liposarcoma. Most MLS/RCLS carry a t(12;16) translocation, resulting in a FUS-DDIT3 fusion gene. We investigated the role of the FUS-DDIT3 fusion in the development of MLS/RCLS in FUS-DDIT3- and DDIT3-transfected human HT1080 sarcoma cells. Cells expressing FUS-DDIT3 and DDIT3 grew as liposarcomas in severe combined immunodeficient mice and exhibited a capillary network morphology that was similar to networks of MLS/RCLS. Microarray-based comparison of HT1080, the transfected cells, and an MLS/RCLS-derived cell line showed that the FUS-DDIT3- and DDIT3-transfected variants shifted toward an MLS/RCLS-like expression pattern. DDIT3-transfected cells responded in vitro to adipogenic factors by accumulation of fat and transformation to a lipoblast-like morphology. In conclusion, because the fusion oncogene FUS-DDIT3 and the normal DDIT3 induce a liposarcoma phenotype when expressed in a primitive sarcoma cell line, MLS/RCLS may develop from cell types other than preadipocytes. This may explain the preferential occurrence of MLS/RCLS in nonadipose tissues. In addition, development of lipoblasts and the typical MLS/RCLS capillary network could be an effect of the DDIT3 transcription factor partner of the fusion oncogene.
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| 6. |
- Gouras, Gunnar, et al.
(författare)
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Critical role of intraneuronal A beta in Alzheimer's disease: Technical challenges in studying intracellular A beta
- 2012
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Ingår i: Life Sciences. - : Elsevier BV. - 1879-0631 .- 0024-3205. ; 91:23-24, s. 1153-1158
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Multiple lines of evidence have implicated beta-amyloid (A beta) in the pathogenesis of Alzheimer's disease (AD). However, the mechanism(s) whereby A beta is involved in the disease process remains unclear. The dominant hypothesis in AD has been that A beta initiates the disease via toxicity from secreted, extracellular A beta aggregates. More recently, an alternative hypothesis has emerged focusing on a pool of A beta that accumulates early on within AD vulnerable neurons of the brain. Although the topic of intraneuronal A beta has been of major interest in the field, technical difficulties in detecting intraneuronal A beta have also made this topic remarkably controversial. Here we review evidence pointing to the critical role of intraneuronal A beta in AD and provide insights both into challenges faced in detecting intracellular A beta and the prion-like properties of A beta. Main methods: Immunoprecipitation and Western blot are used for A beta detection. Key findings: We highlight that a standard biochemical method can underestimate intraneuronal A beta and that extracellular A beta can up-regulate intracellular A beta. We also show that detergent can remove intraneuronal A beta. Significance: There is a growing awareness that intraneuronal A beta is a key pathogenic pool of A beta involved in causing synapse dysfunction. Difficulties in detecting intraneuronal A beta are an insufficient reason for ignoring this critical pool of A beta. (C) 2012 Elsevier Inc. All rights reserved.
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| 7. |
- Gouras, Gunnar, et al.
(författare)
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The Inside-Out Amyloid Hypothesis and Synapse Pathology in Alzheimer's Disease.
- 2014
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Ingår i: Neurodegenerative Diseases. - : S. Karger AG. - 1660-2862 .- 1660-2854. ; 13:2-3, s. 142-146
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Tidskriftsartikel (refereegranskat)abstract
- Cumulative evidence in brains and cultured neurons of Alzheimer's disease (AD) transgenic mouse models, as well as in human postmortem AD brains, highlights that age-related increases in β-amyloid peptide (Aβ), particularly in endosomes near synapses, are involved in early synapse dysfunction. Our immunoelectron microscopy and high-resolution immunofluorescence microscopy studies show that this early subcellular Aβ accumulation leads to progressive Aβ aggregation and pathology, particularly within dystrophic neurites and synapses. These studies confirm that neuritic/synaptic Aβ accumulation is the nidus of plaque formation. Aβ-dependent synapse pathology in AD models is modulated by synaptic activity and is plaque independent. The amyloid precursor protein (APP) is normally transported down neurites and appears to be preferentially processed to Aβ at synapses. Synapses are sites of early Aβ accumulation and aberrant tau phosphorylation in AD, which alter the synaptic composition at early stages of the disease. Elucidating the normal role of APP, and potentially of Aβ, at synapses should provide important insights into the mechanism(s) of Aβ-induced synapse dysfunction in AD and how to therapeutically mitigate these dysfunctions. © 2013 S. Karger AG, Basel.
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| 8. |
- Klementieva, Oxana, et al.
(författare)
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Detection of pre-plaque amyloid aggregation using FTIR
- 2014
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease (AD) is characterized by misfolding and aggregation of naturally occurring beta-amyloid peptides (Aβ). These aggregates are thought to be pathogenic to neurons, although the conformation of the pathogenic Aβ species remains unclear. Biochemical extraction methods and different microscopy techniques (TEM, confocal) can be used to identify pathogenic Aβ species in the brain, although such methods can alter protein conformation or are n ot designed to determine structural details of protein assemblies.
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| 9. |
- Larsson, Karolina, et al.
(författare)
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Children's use of English as lingua franca in Swedish preschools
- 2023
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Ingår i: Multilingua-Journal of Cross-Cultural and Interlanguage Communication. - : Walter de Gruyter GmbH. - 0167-8507 .- 1613-3684. ; 42:4, s. 527-557
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Forskningsöversikt (refereegranskat)abstract
- This paper highlights a current phenomenon reported from preschools placed in multilingual areas in Sweden, namely that some preschoolers with mutually different language backgrounds sometimes use English as lingua franca instead of Swedish during play. The data stems from a study of language environments in Swedish preschools situated in both monolingual and multilingual areas. The analyses reveal that many children are influenced by the English language in both areas, but to a much greater extent in multilingual areas. An interesting situation arises when the majority language of society, which is also the language of education and lingua franca of the preschool, acquires a less prevailing role in children's accomplishment of everyday practices. Data show that the participating children are exposed to and speak English to a varying extent. They learn and teach each other English, and speak English in an array of pragmatic purposes; to position themselves in the social hierarchies of the preschool group, to create meaning within their shared peer culture and for the purpose of exclusion of intruders. English is also used as a secret language of friendship.
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| 10. |
- Martinsson, Isak, et al.
(författare)
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APP depletion alters selective pre- and post-synaptic proteins
- 2019
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Ingår i: Molecular and Cellular Neuroscience. - : Elsevier BV. - 1044-7431 .- 1095-9327. ; 95, s. 86-95
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Tidskriftsartikel (refereegranskat)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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