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Liberta, F., Loerch, S., Rennegarbege, M., Schierhorn, A., Westermark, P., Westermark, G., . . . Schmidt, M. (2019). Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids. Nature Communications, 10, Article ID 1104.
Open this publication in new window or tab >>Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 1104Article in journal (Refereed) Published
Abstract [en]

Systemic AA amyloidosis is a worldwide occurring protein misfolding disease of humans and animals. It arises from the formation of amyloid fibrils from the acute phase protein serum amyloid A. Here, we report the purification and electron cryo-microscopy analysis of amyloid fibrils from a mouse and a human patient with systemic AA amyloidosis. The obtained resolutions are 3.0 angstrom and 2.7 angstrom for the murine and human fibril, respectively. The two fibrils differ in fundamental properties, such as presence of right-hand or left-hand twisted cross-beta sheets and overall fold of the fibril proteins. Yet, both proteins adopt highly similar beta-arch conformations within the N-terminal similar to 21 residues. Our data demonstrate the importance of the fibril protein N-terminus for the stability of the analyzed amyloid fibril morphologies and suggest strategies of combating this disease by interfering with specific fibril polymorphs.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Cell and Molecular Biology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-379892 (URN)10.1038/s41467-019-09033-z (DOI)000460510000001 ()30846696 (PubMedID)
Funder
EU, Horizon 2020German Research Foundation (DFG), FA 456/15-1German Research Foundation (DFG), SCHM 3276/1
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-03-29Bibliographically approved
Panahi, A. V., Hultman, P., Ollinger, K., Westermark, G. T. & Lundmark, K. (2019). Lipid membranes accelerate amyloid formation in the mouse model of AA amyloidosis. Amyloid: Journal of Protein Folding Disorders, 26(1), 34-44
Open this publication in new window or tab >>Lipid membranes accelerate amyloid formation in the mouse model of AA amyloidosis
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2019 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, no 1, p. 34-44Article in journal (Refereed) Published
Abstract [en]

Introduction:

AA amyloidosis develops as a result of prolonged inflammation and is characterized by deposits of N-terminal proteolytic fragments of the acute phase reactant serum amyloid A (SAA). Macrophages are usually found adjacent to amyloid, suggesting their involvement in the formation and/or degradation of the amyloid fibrils. Furthermore, accumulating evidence suggests that lipid membranes accelerate the fibrillation of different amyloid proteins.

Methods:

Using an experimental mouse model of AA amyloidosis, we compared the amyloidogenic effect of liposomes and/or amyloid-enhancing factor (AEF). Inflammation was induced by subcutaneous injection of silver nitrate followed by intravenous injection of liposomes and/or AEF to accelerate amyloid formation.

Results:

We showed that liposomes accelerate amyloid formation in inflamed mice, but the amyloidogenic effect of liposomes was weaker compared with AEF. Regardless of the induction method, amyloid deposits were mainly found in the marginal zones of the spleen and coincided with the depletion of marginal zone macrophages, while red pulp macrophages and metallophilic marginal zone macrophages proved insensitive to amyloid deposition.

Conclusions:

We conclude that increased intracellular lipid content facilitates AA amyloid fibril formation and show that the mouse model of AA amyloidosis is a suitable system for further mechanistic studies.

Keywords
Amyloid, liposomes, lipid membrane, macrophages, AA amyloidosis
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-383486 (URN)10.1080/13506129.2019.1576606 (DOI)000466218300001 ()30929476 (PubMedID)
Available from: 2019-05-16 Created: 2019-05-16 Last updated: 2019-05-16Bibliographically approved
Westermark, G., Faendrich, M., Lundmark, K. & Westermark, P. (2018). Noncerebral Amyloidoses: Aspects on Seeding, Cross-Seeding, and Transmission. Cold Spring Harbor Perspectives in Medicine, 8(1), Article ID a024323.
Open this publication in new window or tab >>Noncerebral Amyloidoses: Aspects on Seeding, Cross-Seeding, and Transmission
2018 (English)In: Cold Spring Harbor Perspectives in Medicine, ISSN 0103-3247, E-ISSN 2157-1422, Vol. 8, no 1, article id a024323Article in journal (Refereed) Published
Abstract [en]

More than 30 proteins form amyloid in humans, most of them outside of the brain. Deposition of amyloid in extracerebral tissues is very common and seems inevitable for an aging person. Most deposits are localized, small, and probably without consequence, but in some instances, they are associated with diseases such as type 2 diabetes. Other extracerebral amyloidoses are systemic, with life-threatening effects on the heart, kidneys, and other organs. Here, we review how amyloid may spread through seeding and whether transmission of amyloid diseases may occur between humans. We also discuss whether cross-seeding is important in the development of amyloidosis, focusing specifically on the amyloid proteins AA, transthyretin, and islet amyloid polypeptide (IAPP).

Place, publisher, year, edition, pages
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2018
National Category
Cell and Molecular Biology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-351767 (URN)10.1101/cshperspect.a024323 (DOI)000429143200001 ()
Funder
Swedish Research CouncilErik, Karin och Gösta Selanders FoundationSwedish Diabetes AssociationGerman Research Foundation (DFG), FA 456/15-1
Available from: 2018-06-04 Created: 2018-06-04 Last updated: 2019-03-29Bibliographically approved
Rahman, M. M., Westermark, G., Zetterberg, H., Hard, T. & Sandgren, M. (2018). Protofibrillar and Fibrillar Amyloid-beta Binding Proteins in Cerebrospinal Fluid. Journal of Alzheimer's Disease, 66(3), 1053-1064
Open this publication in new window or tab >>Protofibrillar and Fibrillar Amyloid-beta Binding Proteins in Cerebrospinal Fluid
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2018 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 66, no 3, p. 1053-1064Article in journal (Refereed) Published
Abstract [en]

Aggregation and deposition of misfolded amyloid-beta (A beta) peptide in the brain is central to Alzheimer's disease (AD). Oligomeric, protofibrillar, and fibrillar forms of A beta are believed to be neurotoxic and cause neurodegeneration in AD, but the toxicity mechanisms are not well understood and may involve A beta-interacting molecular partners. In a previous study, we identified potential A beta(42) protofibrillar-binding proteins in serum and cerebrospinal fluid (CSF) using an engineered version of A beta(42) (A beta 42CC) that forms protofibrils, but not fibrils. Here we studied binding of proteins to A beta(42) fibrils in AD and non-AD CSF and compared these with protofibrillar A beta 42CC-binding partners. A beta(42) fibrils sequestered 2.4-fold more proteins than A beta 42CC protofibrils. Proteins with selective binding to fibrillar aggregates with low nanomolar affinity were identified. We also found that protofibrillar and fibrillar A beta-binding proteins represent distinct functional categories. A beta 42CC protofibrils triggered interactions with proteins involved in catalytic activities, like transferases and oxidoreductases, while A beta(42) fibrils were more likely involved in binding to proteoglycans, growth factors and neuron-associated proteins, e.g., neurexin-1, -2, and -3. Interestingly, 10 brain-enriched proteins were identified among the fibril-binding proteins, while protofibril-extracted proteins had more general expression patterns. Both types of A beta aggregates bound several extracellular proteins. Additionally, we list a set of CSF proteins that might have potential to discriminate between AD and non-AD CSF samples. The results may be of relevance both for biomarker studies and for studies of A beta-related toxicity mechanisms.

Keywords
Alzheimer's disease, amyloid-beta, biomolecular interaction, cerebrospinal fluid, fibrils, protofibrils
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-372429 (URN)10.3233/JAD-180596 (DOI)000451225400015 ()30372682 (PubMedID)
Funder
Swedish Research Council Formas, 942-2015-945Swedish Research CouncilEU, European Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved
Oskarsson, M. E., Hermansson, E., Wang, Y., Welsh, N., Presto, J., Johansson, J. & Westermark, G. (2018). The BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells. Proceedings of the National Academy of Sciences of the United States of America, 115(12), E2752-E2761
Open this publication in new window or tab >>The BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 12, p. E2752-E2761Article in journal (Refereed) Published
Abstract [en]

Aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils in islets of Langerhans is associated with type 2 diabetes, and formation of toxic IAPP species is believed to contribute to the loss of insulin-producing beta cells. The BRICHOS domain of integral membrane protein 2B (Bri2), a transmembrane protein expressed in several peripheral tissues and in the brain, has recently been shown to prevent fibril formation and toxicity of Aβ42, an amyloid-forming peptide in Alzheimer disease. In this study, we demonstrate expression of Bri2 in human islets and in the human beta-cell line EndoC-βH1. Bri2 colocalizes with IAPP intracellularly and is present in amyloid deposits in patients with type 2 diabetes. The BRICHOS domain of Bri2 effectively inhibits fibril formation in vitro and instead redirects IAPP into formation of amorphous aggregates. Reduction of endogenous Bri2 in EndoC-βH1 cells with siRNA increases sensitivity to metabolic stress leading to cell death while a concomitant overexpression of Bri2 BRICHOS is protective. Also, coexpression of IAPP and Bri2 BRICHOS in lateral ventral neurons of Drosophila melanogaster results in an increased cell survival. IAPP is considered to be the most amyloidogenic peptide known, and described findings identify Bri2, or in particular its BRICHOS domain, as an important potential endogenous inhibitor of IAPP aggregation and toxicity, with the potential to be a possible target for the treatment of type 2 diabetes.

Keywords
Bri2, BRICHOS, chaperone, IAPP, amyloid, islet amyloid, beta cells, type 2 diabetes
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-265483 (URN)10.1073/pnas.1715951115 (DOI)000427829500014 ()
Funder
Swedish Research CouncilSwedish Diabetes AssociationNovo NordiskErnfors Foundation
Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2018-06-01Bibliographically approved
Carlsson, P.-O., Espes, D., Sedigh, A., Rotem, A., Zimermann, B., Grinberg, H., . . . Korsgren, O. (2018). Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus. American Journal of Transplantation, 18(7), 1735-1744
Open this publication in new window or tab >>Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus
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2018 (English)In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 18, no 7, p. 1735-1744Article in journal (Refereed) Published
Abstract [en]

Macroencapsulation devices provide the dual possibility to immunoprotect transplanted cells while also being retrievable; the latter bearing importance for safety in future trials with stem-cell derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The βAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the βAir device containing allogeneic human pancreatic islets to patients with type 1 diabetes. Four patients were transplanted with 1-2 βAir devices, each containing 155000-180000 IEQ (i.e. 1800-4600 IEQ per kg body weight), and monitored for 3-6 months, followed by the recovery of devices. Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose-stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the βAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited.

Keywords
cellular biology, clinical research, practice, diabetes: type 1, encapsulation, endocrinology, diabetology, islet transplantation, islets of Langerhans, translational research, science
National Category
Endocrinology and Diabetes Surgery Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-337701 (URN)10.1111/ajt.14642 (DOI)000437727800020 ()29288549 (PubMedID)
Funder
Ernfors FoundationSwedish Diabetes AssociationSwedish Research Council, 921-2014-7054Swedish Research Council, K2013-55X-15043Swedish Research Council, K2015-54X-12219-19-4Swedish Research Council, K2016-01040Swedish Research Council, K2016-GTWNovo NordiskSwedish Child Diabetes FoundationEU, European Research Council, F4-2013-602889EU, European Research Council, 646075-ELASTISLETEXODIAB - Excellence of Diabetes Research in Sweden
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2018-01-03 Created: 2018-01-03 Last updated: 2019-07-03Bibliographically approved
Krizhanovskii, C., Fred, R. G., Oskarsson, M. E., Westermark, G. T. & Welsh, N. (2017). Addition of exogenous sodium palmitate increases the IAPP/insulin mRNA ratio via GPR40 in human EndoC-beta H1 cells. Upsala Journal of Medical Sciences, 122(3), 149-159
Open this publication in new window or tab >>Addition of exogenous sodium palmitate increases the IAPP/insulin mRNA ratio via GPR40 in human EndoC-beta H1 cells
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2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 3, p. 149-159Article in journal (Refereed) Published
Abstract [en]

Background: Enhanced IAPP production may contribute to islet amyloid formation in type 2 diabetes. The objective of this study was to determine the effects of the saturated fatty acid palmitate on IAPP levels in human beta-cells. Methods: EndoC-beta H1 cells and human islets were cultured in the presence of sodium palmitate. Effects on IAPP/insulin mRNA expression and secretion were determined using real-time qPCR/ELISA. Pharmacological activators and/or inhibitors and RNAi were used to determine the underlying mechanisms. Results: We observed that EndoC-beta H1 cells exposed to palmitate for 72 h displayed decreased expression of Pdx-1 and MafA and increased expression of thioredoxin-interacting protein (TXNIP), reduced insulin mRNA expression and glucose-induced insulin secretion, as well as increased IAPP mRNA expression and secretion. Further, these effects were independent of fatty acid oxidation, but abolished in response to GPR40 inhibition/downregulation. In human islets both a high glucose concentration and palmitate promoted increased IAPP mRNA levels, resulting in an augmented IAPP/insulin mRNA ratio. This was paralleled by elevated IAPP/insulin protein secretion and content ratios. Conclusions: Addition of exogenous palmitate to human beta-cells increased the IAPP/insulin expression ratio, an effect contributed to by activation of GPR40. These findings may be pertinent to our understanding of the islet amyloid formation process.

Keywords
Amyloid, fatty acids, insulin, islet amyloid polypeptide (IAPP), palmitate
National Category
Cell and Molecular Biology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-340975 (URN)10.1080/03009734.2017.1368745 (DOI)000414107800001 ()28980863 (PubMedID)
Available from: 2018-02-06 Created: 2018-02-06 Last updated: 2018-02-06Bibliographically approved
Krotee, P., Rodriguez, J. A., Sawaya, M. R., Cascio, D., Reyes, F. E., Shi, D., . . . Eisenberg, D. S. (2017). Atomic structures of fibrillar segments of hIAPP suggest tightly mated beta-sheets are important or cytotoxicity. eLIFE, 6
Open this publication in new window or tab >>Atomic structures of fibrillar segments of hIAPP suggest tightly mated beta-sheets are important or cytotoxicity
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2017 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 6Article in journal (Refereed) Published
Abstract [en]

hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic beta-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19-29 S20G, forms pairs of beta-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15-25 WT, forms non-toxic labile beta-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19-29 S20G may serve as a model for the toxic spine of hIAPP.

National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-316042 (URN)10.7554/eLife.19273 (DOI)000392186000001 ()
Funder
NIH (National Institute of Health), R01 AG029430
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2018-01-13Bibliographically approved
Rostami, J., Holmqvist, S., Lindström, V., Sigvardson, J., Westermark, G., Ingelsson, M., . . . Erlandsson, A. (2017). Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes. Journal of Neuroscience, 37(49), 11835-11853
Open this publication in new window or tab >>Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes
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2017 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 37, no 49, p. 11835-11853Article in journal (Refereed) Published
Abstract [en]

Many lines of evidence suggest that the Parkinson's disease (PD)-related protein alpha-synuclein (alpha-SYN) can propagate from cell to cell in a prion-like manner. However, the cellular mechanisms behind the spreading remain elusive. Here, we show that human astrocytes derived from embryonic stem cells actively transfer aggregated alpha-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes' lysosomal digestion of excess alpha-SYN oligomers results in alpha-SYN deposits in the trans-Golgi network followed by endoplasmic reticulum swelling and mitochondrial disturbances. The stressed astrocytes respond by conspicuously sending out TNTs, enabling intercellular transfer of alpha-SYN to healthy astrocytes, which in return deliver mitochondria, indicating a TNT-mediated rescue mechanism. Using a pharmacological approach to inhibit TNT formation, we abolished the transfer of both alpha-SYN and mitochondria. Together, our results highlight the role of astrocytes in alpha-SYN cell-to-cell transfer, identifying possible pathophysiological events in the PD brain that could be of therapeutic relevance.

Place, publisher, year, edition, pages
SOC NEUROSCIENCE, 2017
Keywords
alpha-synuclein, astrocytes, lysosomes, mitochondria, trans-Golgi, tunneling nanotubes
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-340258 (URN)10.1523/JNEUROSCI.0983-17.2017 (DOI)000418053700007 ()29089438 (PubMedID)
Funder
Swedish Research CouncilThe Crafoord FoundationÅke Wiberg Foundation
Available from: 2018-01-31 Created: 2018-01-31 Last updated: 2018-01-31Bibliographically approved
Ullsten, S., Bohman, S., Oskarsson, M. E., Nilsson, K. P., Westermark, G. & Carlsson, P.-O. (2017). Islet amyloid deposits preferentially in the highly functional and most blood-perfused islets.. Endocrine Connections, 6(7), 458-468
Open this publication in new window or tab >>Islet amyloid deposits preferentially in the highly functional and most blood-perfused islets.
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2017 (English)In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 6, no 7, p. 458-468Article in journal (Refereed) Published
Abstract [en]

Islet amyloid and beta cell death in type 2 diabetes are heterogeneous events, where some islets are affected early in the disease process, whereas others remain visibly unaffected. This study investigated the possibility that inter-islet functional and vascular differences may explain the propensity for amyloid accumulation in certain islets. Highly blood-perfused islets were identified by microspheres in human islet amyloid polypeptide expressing mice fed a high-fat diet for three or 10 months. These highly blood-perfused islets had better glucose-stimulated insulin secretion capacity than other islets and developed more amyloid deposits after 10 months of high-fat diet. Similarly, human islets with a superior release capacity formed more amyloid in high glucose culture than islets with a lower release capacity. The amyloid formation in mouse islets was associated with a higher amount of prohormone convertase 1/3 and with a decreased expression of its inhibitor proSAAS when compared to islets with less amyloid. In contrast, levels of prohormone convertase 2 and expression of its inhibitor neuroendocrine protein 7B2 were unaltered. A misbalance in prohormone convertase levels may interrupt the normal processing of islet amyloid polypeptide and induce amyloid formation. Preferential amyloid load in the most blood-perfused and functional islets may accelerate the progression of type 2 diabetes.

Keywords
blood flow, heterogeneity, islet amyloid, pancreatic islets
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-330801 (URN)10.1530/EC-17-0148 (DOI)000411647000007 ()28790139 (PubMedID)
Funder
Swedish Research Council, 55X-15043Swedish Child Diabetes FoundationSwedish Diabetes AssociationNovo NordiskEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-12-18Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-1151-9986

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