| 1. |
- Aguilar-Calvo, Patricia, et al.
(författare)
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Generation of novel neuroinvasive prions following intravenous challenge
- 2018
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Ingår i: Brain Pathology. - : WILEY. - 1015-6305 .- 1750-3639. ; 28:6, s. 999-1011
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Tidskriftsartikel (refereegranskat)abstract
- Prions typically spread into the central nervous system (CNS), likely via peripheral nerves. Yet prion conformers differ in their capacity to penetrate the CNS; certain fibrillar prions replicate persistently in lymphoid tissues with no CNS entry, leading to chronic silent carriers. Subclinical carriers of variant Creutzfeldt-Jakob (vCJD) prions in the United Kingdom have been estimated at 1:2000, and vCJD prions have been transmitted through blood transfusion, however, the circulating prion conformers that neuroinvade remain unclear. Here we investigate how prion conformation impacts brain entry of transfused prions by challenging mice intravenously to subfibrillar and fibrillar strains. We show that most strains infiltrated the brain and caused terminal disease, however, the fibrillar prions showed reduced CNS entry in a strain-dependent manner. Strikingly, the highly fibrillar mCWD prion strain replicated in the spleen and emerged in the brain as a novel strain, indicating that a new neuroinvasive prion had been generated from a previously non-neuroinvasive strain. The new strain showed altered plaque morphology, brain regions targeted and biochemical properties and these properties were maintained upon intracerebral passage. Intracerebral passage of prion-infected spleen re-created the new strain. Splenic prions resembled the new strain biochemically and intracerebral passage of prion-infected spleen re-created the new strain, collectively suggesting splenic prion replication as a potential source. Taken together, these results indicate that intravenous exposure to prion-contaminated blood or blood products may generate novel neuroinvasive prion conformers and disease phenotypes, potentially arising from prion replication in non-neural tissues or from conformer selection.
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| 2. |
- Elgland, Mathias, 1987-
(författare)
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Synthesis and application of β-configured [18/19F]FDGs : Novel prosthetic CuAAC click chemistry fluoroglycosylation tools for amyloid PET imaging and cancer theranostics
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Positron emission tomography (PET) is a non-invasive imaging method that renders three-dimensional images of tissue that selectively has taken up a radiolabelled organic compound, referred to as a radiotracer. This excellent technique provides clinicians with a tool to monitor disease progression and to evaluate how the patient respond to treatment. The by far most widely employed radiotracer in PET is called 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), which is often referred to as the golden standard in PET. From a molecular perspective, [18F]FDG is an analogue of glucose where a hydroxyl group has been replaced with a radioactive fluorine atom (18F). It is well known that covalent attachment of carbohydrates (i.e., glycosylation) to biomolecules tend to improve their properties in the body, in terms of; improved pharmacokinetics, increased metabolic stability and faster clearance from blood and other non-specific tissue. It is therefore natural to pursuit the development of a [18F]fluoroglycosylation method where [18F]FDG is chemically conjugated to a ligand with high affinity for a given biological target (e.g., tumors or disease-associated protein aggregates).This thesis describes a novel [18F]fluoroglycosylation method that in a simple and general manner facilitate the conjugation of [18F]FDG to biological ligands using click chemistry. The utility of the developed [18F]fluoroglycosylation method is demonstrated by radiolabelling of curcumin, thus forming a tracer that may be employed for diagnosis of Alzheimer’s disease. Moreover, a set of oligothiophenes were fluoroglycosylated for potential diagnosis of Alzheimer’s disease but also for other much rarer protein misfolding diseases (e.g., Creutzfeldt-Jakob disease and systemic amyloidosis). In addition, the synthesis of a series of 19F-fluoroglycosylated porphyrins is described which exhibited promising properties not only to detect but also to treat melanoma cancer. Lastly, the synthesis of a set of 19F-fluorinated E-stilbenes, structurally based on the antioxidant resveratrol is presented. The E-stilbenes were evaluated for their capacity to spectrally distinguish between native and protofibrillar transthyretin in the pursuit of finding diagnostic markers for the rare but severe disease, transthyretin amyloidosis.
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| 3. |
- Fändrich, M., et al.
(författare)
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Amyloid fibril polymorphism: a challenge for molecular imaging and therapy
- 2018
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Ingår i: Journal of Internal Medicine. - : WILEY. - 0954-6820 .- 1365-2796. ; 283:3, s. 218-237
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Tidskriftsartikel (refereegranskat)abstract
- The accumulation of misfolded proteins (MPs), both unique and common, for different diseases is central for many chronic degenerative diseases. In certain patients, MP accumulation is systemic (e.g. TTR amyloid), and in others, this is localized to a specific cell type (e.g. Alzheimers disease). In neurodegenerative diseases, NDs, it is noticeable that the accumulation of MP progressively spreads throughout the nervous system. Our main hypothesis of this article is that MPs are not only markers but also active carriers of pathogenicity. Here, we discuss studies from comprehensive molecular approaches aimed at understanding MP conformational variations (polymorphism) and their bearing on spreading of MPs, MP toxicity, as well as MP targeting in imaging and therapy. Neurodegenerative disease (ND) represents a major and growing societal challenge, with millions of people worldwide suffering from Alzheimers or Parkinsons diseases alone. For all NDs, current treatment is palliative without addressing the primary cause and is not curative. Over recent years, particularly the shape-shifting properties of misfolded proteins and their spreading pathways have been intensively researched. The difficulty in addressing ND has prompted most major pharma companies to severely downsize their nervous system disorder research. Increased academic research is pivotal for filling this void and to translate basic research into tools for medical professionals. Recent discoveries of targeting drug design against MPs and improved model systems to study structure, pathology spreading and toxicity strongly encourage future studies along these lines to provide an opportunity for selective imaging, prognostic diagnosis and therapy.
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| 4. |
- Hammarström, Per, 1960-
(författare)
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Anti-Judaism or antisemitism? : The Swedish Association for Mission among the Jews as a Case Study
- 2018
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- De senaste decenniernas forskning om antisemitism i Sverige har i hög grad varit inriktad på utvecklingen under 1900-talet, inte minst problem kopplade till andra världskriget och förhållandet till Nazityskland. Åtskilliga värdefulla resultat har presenterats men flera kapitel återstår att skriva av den svenska antisemitismens historia. Inte minst förtjänar utvecklingen under 1800-talets senare en djupare genomlysning.På 1870-tet bidrog den ekonomiska krisen i Väst- och Centraleuropa till att liberalismen förlorade prestige och ersattes av en totalitär och exkluderande nationalism som legitimerande statsideologi. I fråga om judarna ställde en växande antisemitisk rörelse krav på uppbrott från den tidigare emancipations- och integrationslinjen. Frågan var inte längre hur judar skulle bli en del av nationen utan om det överhuvudtaget var möjligt.Under detta skede omformades traditionellt kristna antijudiska teman till rasistiskt färgad antisemitism om judisk världsmakt. Katolska medier såväl som protestantiska demagoger var många gånger drivande i den antisemitiska rörelsen, samtidigt som delar av kyrkan såg med oro på utvecklingen och snarare höll fast vid en linje där omvändelse och dop sågs som lösningen av den ”judiska frågan”.Mot bakgrund av den tecknade historiska kontexten kommer mitt paper diskutera brytningen mellan kristen antijudaism och modern antisemitism i ett svenskt perspektiv. Jag tar avstamp i en analys av två längre artiklar publicerade på 1880-talet i en lågkyrklig missionstridskrift, Missionstidskrift för Israel. I texterna blandas traditionella teman med samtidens konspiratoriska föreställningar om judisk kontroll över banksystemet, börsen och pressen. Ett framtidsscenario målas, dels om ett judiskt skräckvälde som håller på att upprättas, dels om hela Israels omvändelse och en ny världsordning där en fullkomnad mänsklighet framträder.
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| 5. |
- Jonsson, Frida, et al.
(författare)
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Are neighbourhood inequalities in adult health explained by socio-economic and psychosocial determinants in adolescence and the subsequent life course in northern Sweden? : A decomposition analysis
- 2018
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Ingår i: Health and Place. - : Elsevier. - 1353-8292 .- 1873-2054. ; 52, s. 127-134
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Tidskriftsartikel (refereegranskat)abstract
- This study explains neighbourhood deprivation inequalities in adult health for a northern Swedish cohort by examining the contribution of socio-economic and psychosocial determinants from adolescence (age 16), young adulthood (age 21) and midlife (age 42) to the disparity. Self-reported information from 873 participants was drawn from questionnaires, with complementary neighbourhood register data. The concentration index was used to estimate the inequality while decomposition analyses were run to attribute the disparity to its underlying determinants. The results suggest that socio-economic and psychosocial factors in midlife explain a substantial part, but also that the inequality can originate from conditions in adolescence and young adulthood.
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| 6. |
- Jonsson, Frida, 1988-
(författare)
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The presence of the past : a life course approach to the social determinants of health and health inequalities in northern Sweden
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Positioned at the intersection between the social and life course epidemiological sub-fields, this thesis builds on the idea that the health implications of life and living conditions can extend over years and decades before becoming expressed in the population patterns of ill-health. The overall purpose was to assess how multiple types of social determinants of health across the life course may contribute to ill-health and health inequalities in midlife. Several gaps in knowledge served as the basis for four research questions that focused on: 1) the intermediate role of socio-economic, material and psychosocial factors in young adulthood, in the long-term association between adolescent socio-economic position and midlife ill-health; 2) the implications of poor social capital in adolescence and accumulated over the life course for midlife ill-health; 3) the consequences of intra-generational social mobility for midlife ill-health and 4) the contribution of socio-economic, material and psychosocial circumstances in adolescence, young adulthood and middle-age to midlife neighbourhood deprivation inequalities in ill-health.Methods: The setting of the thesis is Sweden spanning over nearly three decades, from the early 1980s and until the mid-2010s. With information drawn from the Northern Swedish Cohort the study population consists of 1,083 pupils (506 girls and 577 boys) who attended, or should have attended, the last year of compulsory school in 1981. The data used came from questionnaires answered by the participants in the follow-ups at the ages of 16 (in 1981), 21 (in 1986), 30 (in 1995) and 42 (in 2007). The attrition rate was low with 1,010 out of the 1,071 students who were alive over the 26-years participated in all waves (94.3%). Data was also included from the Swedish registers for the same ages as the surveys on the participants’ neighbourhoods and sociodemographic characteristics on all other residents in these areas. The health outcome was functional somatic symptoms, referring to the occurrence of common physical complaints such as musculoskeletal pain, headache, palpitations and fatigue. To capture various social determinants of health, socio-economic, material and psychosocial factors were operationalised as main exposures. The research questions were analysed using: 1) path analysis, 2) multiple linear regression, 3) diagonal reference models and 4) a decomposition analysis.Results: With regard to the four research questions, the results firstly indicated that the long-term association between adolescent socio-economic position and midlife ill-health was linked by socio-economic position in young adulthood and further via material and psychosocial factors in middle-age. Secondly, that poor social capital in adolescence also could play a role in the development of adult illhealth, but that this influence seem to be largely dependent on recent or current conditions in adulthood. Thirdly, that downward mobility in the socio-economic hierarchy during middle-age may have little to no health implications, while upward movements could have a small positive effect on health. Fourthly, that ill-health was concentrated in more socio-economically deprived neighbourhoods and that this inequality was to a small extent attributed to conditions in earlier life period and mainly to factors in adulthood.Conclusions: Based on patterns cutting across the original research questions, the findings from this thesis indicate broadly that socio-economic, material and psychosocial conditions may be meaningful for midlife ill-health and health disparities, jointly and independently from each other. The results also suggests that determinants in the present on the surface appear to be more important for midlife ill-health and health inequalities than those of the past, but at the same time that life circumstances in the earlier life course may not be irrelevant. Rather than representing permanent or resilient health implications, however, the long-term influence of adolescent conditions seem to reflect mainly social processes that are conditional on recent or concurrent adult factors. In sum, the results indicate that a continuum of various life and living conditions may be a key phenomenon underlying ill-health and health disparities in midlife. Specifically, this thesis illustrates how the past may become part of the present through the accumulation and chains of unfavourable circumstances over the life course and conversely, how the present health reflects and embodies a life-long past.
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| 7. |
- Jonsson, Maria, et al.
(författare)
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Aggregated Aβ1-42 Is Selectively Toxic for Neurons, Whereas Glial Cells Produce Mature Fibrils with Low Toxicity in Drosophila
- 2018
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Ingår i: Cell Chemical Biology. - Cambridge, United States : Elsevier BV. - 2451-9456 .- 2451-9448. ; 25:5
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Tidskriftsartikel (refereegranskat)abstract
- The basis for selective vulnerability of certain cell types for misfolded proteins (MPs) in neurodegenerative diseases is largely unknown. This knowledge is crucial for understanding disease progression in relation to MPs spreading in the CNS. We assessed this issue in Drosophila by cell-specific expression of human Aβ1-42 associated with Alzheimer's disease. Expression of Aβ1-42 in various neurons resulted in concentration-dependent severe neurodegenerative phenotypes, and intraneuronal ring-tangle-like aggregates with immature fibril properties when analyzed by aggregate-specific ligands. Unexpectedly, expression of Aβ1-42 from a pan-glial driver produced a mild phenotype despite massive brain load of Aβ1-42 aggregates, even higher than in the strongest neuronal driver. Glial cells formed more mature fibrous aggregates, morphologically distinct from aggregates found in neurons, and was mainly extracellular. Our findings implicate that Aβ1-42 cytotoxicity is both cell and aggregate morphotype dependent. Jonson et al. used transgenic Drosophila to understand cell-specific response to protein aggregates in neurodegenerative disease. They demonstrate that the Alzheimer-associated peptide Aβ1-42 form various amyloid structures with different toxic properties when expressed in different cell types of the brain. © 2018 Elsevier Ltd
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| 8. |
- Khodaparast, Ladan, et al.
(författare)
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Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis
- 2018
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow. In addition, the approach is effective against drug-resistant clinical isolates of Escherichia coli and Acinetobacter baumannii, reducing bacterial load in a murine bladder infection model. Our results indicate that redundant APRs are weak points of bacterial protein homeostasis and that targeting these may be an attractive antibacterial strategy.
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| 9. |
- Michno, Wojciech, 1992, et al.
(författare)
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Multimodal Chemical Imaging of Amyloid Plaque Polymorphism Reveals A beta Aggregation Dependent Anionic Lipid Accumulations and Metabolism
- 2018
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 90:13, s. 8130-8138
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid plaque formation constitutes one of the main pathological hallmarks of Alzheimer's disease (AD) and is suggested to be a critical factor driving disease pathogenesis. Interestingly, in patients that display amyloid pathology but remain cognitively normal, A beta deposits are predominantly of diffuse morphology suggesting that cored plaque formation is primarily associated with cognitive deterioration and AD pathogenesis. Little is known about the molecular mechanism responsible for conversion of monomeric A beta into neurotoxic aggregates and the predominantly cored deposits observed in AD. The structural diversity among A beta plaques, including cored/compact- and diffuse, may be linked to their distinct A beta profile and other chemical species including neuronal lipids. We developed a novel, chemical imaging paradigm combining matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) and fluorescent amyloid staining. This multimodal imaging approach was used to probe the lipid chemistry associated with structural plaque heterogeneity in transgenic AD mice (tgAPP(Swe)) and was correlated to A beta profiles determined by subsequent laser microdissection and immunoprecipitation-mass spectrometry. Multivariate image analysis revealed an inverse localization of ceramides and their matching metabolites to diffuse and cored structures within single plaques, respectively. Moreover, phosphatidylinositols implicated in AD pathogenesis, were found to localize to the diffuse A beta structures and correlate with A beta 1-42. Further, lysophospholipids implicated in neuroinflammation were increased in all A beta deposits. The results support previous clinical findings on the importance of lipid disturbances in AD pathophysiology and associated sphingolipid processing. These data highlight the potential of multimodal imaging as a powerful technology to probe neuropathological mechanisms.
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| 10. |
- Nilsson, Peter, 1970-, et al.
(författare)
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Luminescent-Conjugated Oligothiophene Probe Applications for Fluorescence Imaging of Pure Amyloid Fibrils and Protein Aggregates in Tissues
- 2018
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Ingår i: Amyloid Proteins. - New York, NY : Humana Press. - 9781493978151 - 9781493978168 ; , s. 485-496
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Bokkapitel (refereegranskat)abstract
- Luminescent-conjugated oligo- and polythiophenes (LCOs and LCPs) are valuable tools for optical imaging of a plethora of protein aggregates associated with amyloidoses. Here, we outline updated protocols for the application of the anionic pentameric LCO, p-FTAA, for staining and hyperspectral imaging of protein aggregates in a variety of settings such as in vitro formed amyloid fibrils, ex vivo tissue sections, and whole brain Drosophila.
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