| 1. |
- Qi, Xingmei, et al.
(författare)
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Spider silk protein forms amyloid-like nanofibrils through a non-nucleation-dependent polymerization mechanism
- 2023
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Ingår i: Small. - : John Wiley & Sons. - 1613-6810 .- 1613-6829. ; 18:46
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid fibrils—nanoscale fibrillar aggregates with high levels of order—are pathogenic in some today incurable human diseases; however, there are also many physiologically functioning amyloids in nature. The process of amyloid formation is typically nucleation-elongation-dependent, as exemplified by the pathogenic amyloid-β peptide (Aβ) that is associated with Alzheimer's disease. Spider silk, one of the toughest biomaterials, shares characteristics with amyloid. In this study, it is shown that forming amyloid-like nanofibrils is an inherent property preserved by various spider silk proteins (spidroins). Both spidroins and Aβ capped by spidroin N- and C-terminal domains, can assemble into macroscopic spider silk-like fibers that consist of straight nanofibrils parallel to the fiber axis as observed in native spider silk. While Aβ forms amyloid nanofibrils through a nucleation-dependent pathway and exhibits strong cytotoxicity and seeding effects, spidroins spontaneously and rapidly form amyloid-like nanofibrils via a non-nucleation-dependent polymerization pathway that involves lateral packing of fibrils. Spidroin nanofibrils share amyloid-like properties but lack strong cytotoxicity and the ability to self-seed or cross-seed human amyloidogenic peptides. These results suggest that spidroins' unique primary structures have evolved to allow functional properties of amyloid, and at the same time direct their fibrillization pathways to avoid formation of cytotoxic intermediates.
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| 2. |
- Qi, Xingmei, et al.
(författare)
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Spider Silk Protein Forms Amyloid-Like Nanofibrils through a Non-Nucleation-Dependent Polymerization Mechanism (Small 46/2023)
- 2023
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Ingår i: Small. - : Wiley. - 1613-6810 .- 1613-6829. ; 19:46
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid fibrils—nanoscale fibrillar aggregates with high levels of order—are pathogenic in some today incurable human diseases; however, there are also many physiologically functioning amyloids in nature. The process of amyloid formation is typically nucleation-elongation-dependent, as exemplified by the pathogenic amyloid-β peptide (Aβ) that is associated with Alzheimer's disease. Spider silk, one of the toughest biomaterials, shares characteristics with amyloid. In this study, it is shown that forming amyloid-like nanofibrils is an inherent property preserved by various spider silk proteins (spidroins). Both spidroins and Aβ capped by spidroin N- and C-terminal domains, can assemble into macroscopic spider silk-like fibers that consist of straight nanofibrils parallel to the fiber axis as observed in native spider silk. While Aβ forms amyloid nanofibrils through a nucleation-dependent pathway and exhibits strong cytotoxicity and seeding effects, spidroins spontaneously and rapidly form amyloid-like nanofibrils via a non-nucleation-dependent polymerization pathway that involves lateral packing of fibrils. Spidroin nanofibrils share amyloid-like properties but lack strong cytotoxicity and the ability to self-seed or cross-seed human amyloidogenic peptides. These results suggest that spidroins´ unique primary structures have evolved to allow functional properties of amyloid, and at the same time direct their fibrillization pathways to avoid formation of cytotoxic intermediates.
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| 3. |
- Sarlus, Heela, et al.
(författare)
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Allergy influences the inflammatory status of the brain and enhances tau-phosphorylation
- 2012
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Ingår i: Journal of Cellular and Molecular Medicine (Print). - : Wiley. - 1582-1838 .- 1582-4934. ; 16:10, s. 2401-2412
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Tidskriftsartikel (refereegranskat)abstract
- Despite the existing knowledge regarding the neuropathology of Alzheimer's disease (AD), the cause of sporadic forms of the disease is unknown. It has been suggested that systemic inflammation may have a role, but the exact mechanisms through which inflammatory processes influence the pathogenesis and progress of AD are not obvious. Allergy is a chronic inflammatory disease affecting more than 20% of the Western population, but the effects of allergic conditions on brain functions are largely unknown. The aim of this study was to investigate whether or not chronic peripheral inflammation associated with allergy affects the expression of AD-related proteins and inflammatory markers in the brain. On the basis of previously described models for allergy in mice we developed a model of chronic airway allergy in mouse, with ovalbumin as allergen. The validity of the chronic allergy model was confirmed by a consistent and reproducible eosinophilia in the bronchoalveolar lavage (BAL) fluid of allergic animals. Allergic mice were shown to have increased brain levels of both immunoglobulin (Ig) G and IgE with a widespread distribution. Allergy was also found to increase phosphorylation of tau protein in the brain. The present data support the notion that allergy-dependent chronic peripheral inflammation modifies the brain inflammatory status, and influences phosphorylation of an AD-related protein, indicating that allergy may be yet another factor to be considered for the development and/or progression of neurodegenerative diseases such as AD.
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| 4. |
- Wang, Xiuzhe, et al.
(författare)
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Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells : the OmegAD study
- 2015
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Ingår i: Journal of Lipid Research. - : American Society for Biochemistry and Molecular Biology. - 0022-2275 .- 1539-7262. ; 56:3, s. 674-681
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Tidskriftsartikel (refereegranskat)abstract
- Specialized proresolving mediators (SPMs) induce resolution of inflammation. SPMs are derivatives of n-3 and n-6 PUFAs and may mediate their beneficial effects. It is unknown whether supplementation with PUFAs influences the production of SPMs. Alzheimer's disease (AD) is associated with brain inflammation and reduced levels of SPMs. The OmegAD study is a randomized, double-blind, and placebo-controlled clinical trial on AD patients, in which placebo or a supplement of 1.7 g DHA and 0.6 g EPA was taken daily for 6 months. Plasma levels of arachidonic acid decreased, and DHA and EPA levels increased after 6 months of n-3 FA treatment. Peripheral blood mononuclear cells (PBMCs) were obtained before and after the trial. Analysis of the culture medium of PBMCs incubated with amyloid-β 1-40 showed unchanged levels of the SPMs lipoxin A4 and resolvin D1 in the group supplemented with n-3 FAs, whereas a decrease was seen in the placebo group. The changes in SPMs showed correspondence to cognitive changes. Changes in the levels of SPMs were positively correlated to changes in transthyretin. We conclude that supplementation with n-3 PUFAs for 6 months prevented a reduction in SPMs released from PBMCs of AD patients, which was associated with changes in cognitive function.
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| 5. |
- Wang, Xiuzhe
(författare)
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Resolution of inflammation in Alzheimer’s disease
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inflammation is associated with Alzheimer’s disease (AD), a neurodegenerative disorder with no cure up to date. Ample evidence from studies within various disciplines support that inflammation plays a role in AD. Resolution of inflammation is the end stage of inflammation, where the detrimental effects of inflammation are terminated and tissue healing is initiated. Cutting-edge research has demonstrated that resolution of inflammation is controlled by specialized pro-resolving lipid mediators (SPMs). There is emerging evidence for a role of SPMs in various diseases associated with inflammation. One of the SPMs, neuroprotectin D1 (NPD1) was the first to be found in reduced levels in the brain of AD patients. The aims of this thesis were to investigate the resolution status in AD, the mechanisms therein, and the therapeutic potential. In Paper I, we aimed to answer the fundamental question, whether and how the resolution pathway is altered in AD patients. To this end, we analysed cerebrospinal fluid (CSF) and postmortem samples from AD and non-AD patients. We found that in the CSF and hippocampus of AD patients, the levels of one of the SPMs, lipoxin A4, LXA4 were lower than that in non-AD groups. This was further confirmed by analysis of a smaller number of hippocampal samples with liquid chromatography - tandem mass spectrometry (LC-MS-MS) technique, which also revealed that another SPM, maresin 1 (MaR1) was reduced in AD hippocampus. Furthermore, the CSF levels of LXA4, as well as resolvin D1 (RvD1), were positively correlated to mini mental statement examination (MMSE) scores. The cellular distribution of two SPM receptors, LXA4 receptor/formyl peptide receptor 2 (ALX/FPR2) and chemerin receptor 23 (ChemR23) were also described in the human brain. We then investigated if the abnormal resolution may play a role in the pathogenesis of AD. For this purpose, in Paper II, we used a senescence-accelerated mouse model, SAMP8 mice, to study the balance between inflammation and resolution during an abnormal aging progress, since the primary risk of AD is aging. We found that inflammation in SAMP8 mice increased with age, and was higher than that in age-matched control mice. However, the resolution markers LXA4 and RvD1 remained unchanged upon age in SAMP8 mice, or equal to the levels in control mice. Thus, SAMP8 mice appeared to have an unresponsive resolution during the abnormal aging. We also found that enzymes involved in the synthesis of SPMs were abnormally regulated during aging in SAMP8 mice, and that this was related to amyloid β (Aβ) and tau pathology. In Paper III, we analysed materials from a double-blind, randomized, placebo-controlled clinical trial, where n-3 fatty acids or placebo were orally supplemented to AD patients for 6 months. Peripheral blood mononuclear cells (PBMCs) were obtained before and after the trial, and incubated with Aβ ex vivo. We found that there was reduced production of LXA4 and RvD1 by the Aβ-exposed PBMCs in the placebo group, and that n-3 fatty acid supplementation prevented this reduction. There was a positive correlation between altered levels of plasma transthyretin, and the SPMs released from the PBMCs. Finally, in Paper IV, we investigated the therapeutic potential of a resolution stimulating strategy. Using LC-MS-MS technique, we were able to study a broad range of lipid mediators, and found that MaR1 is also reduced in the entorhinal cortex of AD patients. MaR1, as well as LXA4, RvD1, and NPD1 showed direct neuroprotective effects against staurosporine-induced cell death in vitro, and MaR1 specifically exerted phenotypemodulation effects on human microglial cells, and promoted the phagocytosis of Aβ. In conclusion, we have demonstrated that the resolution pathway is altered in AD, and has a relationship with disease development and pathology. Novel therapeutic strategies based on stimulating resolution should be further investigated.
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