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Horvath, Istvan
Publications (8 of 8) Show all publications
Horvath, I., Iashchishyn, I., Moskalenko, R. A., Wang, C., Warmlander, S. K. T., Wallin, C., . . . Morozova-Roche, L. (2018). Co-aggregation of pro-inflammatory S100A9 with alpha-synuclein in Parkinson's disease: ex vivo and in vitro studies. Journal of Neuroinflammation, 15, Article ID 172.
Open this publication in new window or tab >>Co-aggregation of pro-inflammatory S100A9 with alpha-synuclein in Parkinson's disease: ex vivo and in vitro studies
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2018 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, article id 172Article in journal (Refereed) Published
Abstract [en]

Background: Chronic neuroinflammation is a hallmark of Parkinson's disease (PD) pathophysiology, associated with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascade in Alzheimer's disease. This is the first report on the co-aggregation of alpha-synuclein (alpha-syn) and S100A9 both in vitro and ex vivo in PD brain.

Methods: Single and sequential immunohistochemistry, immunofluorescence, scanning electron and atomic force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and alpha-syn location and aggregation. In vitro studies revealing S100A9 and alpha-syn interaction and co-aggregation were conducted by NMR, circular dichroism, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods.

Results: Co-localized and co-aggregated S100A9 and alpha-syn were found in 20% Lewy bodies and 77% neuronal cells in the substantia nigra; both proteins were also observed in Lewy bodies in PD frontal lobe (Braak stages 4-6). Lewy bodies were characterized by ca. 10-23 mu m outer diameter, with S100A9 and alpha-syn being co-localized in the same lamellar structures. S100A9 was also detected in neurons and blood vessels of the aged patients without PD, but in much lesser extent. In vitro S100A9 and alpha-syn were shown to interact with each other via the alpha-syn C-terminus with an apparent dissociation constant of ca. 5 mu M. Their co-aggregation occurred significantly faster and led to formation of larger amyloid aggregates than the self-assembly of individual proteins. S100A9 amyloid oligomers were more toxic than those of alpha-syn, while co-aggregation of both proteins mitigated the cytotoxicity of S100A9 oligomers.

Conclusions: We suggest that sustained neuroinflammation promoting the spread of amyloidogenic S100A9 in the brain tissues may trigger the amyloid cascade involving alpha-syn and S100A9 and leading to PD, similar to the effect of S100A9 and A beta co-aggregation in Alzheimer's disease. The finding of S100A9 involvement in PD may open a new avenue for therapeutic interventions targeting S100A9 and preventing its amyloid self-assembly in affected brain tissues.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
S100A9, alpha-Synuclein, Parkinson's disease, Neuroinflammation, Amyloid, Cytotoxicity
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-150174 (URN)10.1186/s12974-018-1210-9 (DOI)000434209800001 ()29866153 (PubMedID)
Funder
Västerbotten County Council, ALFVLL-369861Swedish Research Council, 2014-3241The Swedish Brain Foundation
Available from: 2018-07-18 Created: 2018-07-18 Last updated: 2018-07-19Bibliographically approved
Wang, C., Iashchishyn, I., Pansieri, J., Nyström, S., Klementieva, O., Kara, J., . . . Morozova-Roche, L. (2018). S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer's Disease. Scientific Reports, 8, Article ID 12836.
Open this publication in new window or tab >>S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer's Disease
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12836Article in journal (Refereed) Published
Abstract [en]

Pro-inflammatory and amyloidogenic S100A9 protein is an important contributor to Alzheimer's disease (AD) pathology. Traumatic brain injury (TBI) is viewed as a precursor state for AD. Here we have shown that S100A9-driven amyloid-neuroinflammatory cascade was initiated in TBI and may serve as a mechanistic link between TBI and AD. By analyzing the TBI and AD human brain tissues, we demonstrated that in post-TBI tissues S100A9, produced by neurons and microglia, becomes drastically abundant compared to A beta and contributes to both precursor-plaque formation and intracellular amyloid oligomerization. Conditions implicated in TBI, such as elevated S100A9 concentration, acidification and fever, provide strong positive feedback for S100A9 nucleation-dependent amyloid formation and delay in its proteinase clearance. Consequently, both intracellular and extracellular S100A9 oligomerization correlated with TBI secondary neuronal loss. Common morphology of TBI and AD plaques indicated their similar initiation around multiple aggregation centers. Importantly, in AD and TBI we found S100A9 plaques without A beta. S100A9 and A beta plaque pathology was significantly advanced in AD cases with TBI history at earlier age, signifying TBI as a risk factor. These new findings highlight the detrimental consequences of prolonged post-TBI neuroinflammation, which can sustain S100A9-driven amyloid-neurodegenerative cascade as a specific mechanism leading to AD development.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-151784 (URN)10.1038/s41598-018-31141-x (DOI)000442870300014 ()30150640 (PubMedID)
Funder
Swedish Institute
Available from: 2018-09-14 Created: 2018-09-14 Last updated: 2018-09-14Bibliographically approved
Horvath, I., Iashchishyn, I. A., Forsgren, L. & Morozova-Roche, L. A. (2017). Immunochemical Detection of alpha-Synuclein Autoantibodies in Parkinson's Disease: Correlation between Plasma and Cerebrospinal Fluid Levels. ACS Chemical Neuroscience, 8(6), 1170-1176
Open this publication in new window or tab >>Immunochemical Detection of alpha-Synuclein Autoantibodies in Parkinson's Disease: Correlation between Plasma and Cerebrospinal Fluid Levels
2017 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 8, no 6, p. 1170-1176Article in journal (Refereed) Published
Abstract [en]

Autoantibodies to Parkinson's disease (PD) amyloidogenic protein, a-synuclein, were recognized as a prospective biomarker for early disease diagnostics, yet there is inconsistency in previous reports, potentially related to PD status. Therefore, plasma and cerebrospinal fluid (CSF) of the cross-sectional cohort of 60 individuals, including recently diagnosed PD patients with mild and moderate PD and age-matched controls, were examined by enzyme-linked immunosorbent assay (ELISA). Nonparametric statistics was used for data analysis. We found significantly elevated levels of a-synuclein autoantibodies in both plasma and CSF in mild PD compared to controls, followed by some decrease in moderate PD. Receiver operating characteristic and effect size analyses confirmed the diagnostic power of a-synuclein antibodies in both plasma and CSF. For the first time, we showed the correlation between plasma and CSF a-synuclein antibody levels for mild, moderate, and combined PD groups. This indicates the potentiality of a-synuclein antibodies as PD biomarker and the increased diagnostic power of their simultaneous analysis in plasma and CSF.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
Keywords
Biomarkers, blood plasma, cerebrospinal fluid, enzyme-linked immunosorbent assay (ELISA), rkinson's disease, alpha-synuclein autoantibodies
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Neurosciences Pharmaceutical Sciences
Identifiers
urn:nbn:se:umu:diva-137810 (URN)10.1021/acschemneuro.7b00063 (DOI)000404098100008 ()28263550 (PubMedID)
Available from: 2017-07-20 Created: 2017-07-20 Last updated: 2018-06-09Bibliographically approved
Horvath, I., Jia, X., Johansson, P., Wang, C., Moskalenko, R., Steinau, A., . . . Morozova-Roche, L. A. (2016). Pro-inflammatory S100A9 Protein as a Robust Biomarker Differentiating Early Stages of Cognitive Impairment in Alzheimer's Disease [Letter to the editor]. ACS Chemical Neuroscience, 7(1), 34-39
Open this publication in new window or tab >>Pro-inflammatory S100A9 Protein as a Robust Biomarker Differentiating Early Stages of Cognitive Impairment in Alzheimer's Disease
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2016 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 7, no 1, p. 34-39Article in journal, Letter (Refereed) Published
Abstract [en]

Pro-inflammatory protein S100A9 was established as a biomarker of dementia progression and compared with others such as Aβ1-42 and tau-proteins. CSF samples from 104 stringently diagnosed individuals divided into five subgroups were analyzed, including nondemented controls, stable mild cognitive impairment (SMCI), mild cognitive impairment due to Alzheimer's disease (MCI-AD), Alzheimer's disease (AD), and vascular dementia (VaD) patients. ELISA, dot-blotting, and electrochemical impedance spectroscopy were used as research methods. The S100A9 and Aβ1-42 levels correlated with each other: their CSF content decreased already at the SMCI stage and declined further under MCI-AD, AD, and VaD conditions. Immunohistochemical analysis also revealed involvement of both Aβ1-42 and S100A9 in the amyloid-neuroinflammatory cascade already during SMCI. Tau proteins were not yet altered in SMCI; however their contents increased during MCI-AD and AD, diagnosing later dementia stages. Thus, four biomarkers together, reflecting different underlying pathological causes, can accurately differentiate dementia progression and also distinguish AD from VaD.

Keywords
Alzheimer’s disease, mild cognitive impairment, cerebrospinal fluid, S100A9, Aβ1−42, biomarkers, amyloid, inflammation
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-111351 (URN)10.1021/acschemneuro.5b00265 (DOI)000368567200006 ()26550994 (PubMedID)
Available from: 2015-11-13 Created: 2015-11-13 Last updated: 2018-06-07Bibliographically approved
Perdersen, M. N., Fodera, V., Horvath, I., van Maarschalkerweerd, A., Toft, K. N., Weise, C., . . . Vestergaard, B. (2015). Direct Correlation Between Ligand-Induced alpha-Synuclein Oligomers and Amyloid-like Fibril Growth. Scientific Reports, 5, Article ID 10422.
Open this publication in new window or tab >>Direct Correlation Between Ligand-Induced alpha-Synuclein Oligomers and Amyloid-like Fibril Growth
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 10422Article in journal (Refereed) Published
Abstract [en]

Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which are complicated by their transient nature and low population. Here we investigate alpha-synuclein oligomers, enriched by a 2-pyridone molecule (FN075), and the conversion of oligomers into fibrils. As probed by leakage assays, the FN075 induced oligomers potently disrupt vesicles in vitro, suggesting a potential link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed during alpha-synuclein fibrillation. Since the levels of FN075 induced oligomers correlate with the amounts of fibrils among different FN075: protein ratios, the oligomers appear to be on-pathway and modeling supports an 'oligomer stacking model' for alpha-synuclein fibril elongation.

Place, publisher, year, edition, pages
Springer, 2015
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-106505 (URN)10.1038/srep10422 (DOI)000355546300001 ()
Available from: 2015-07-16 Created: 2015-07-14 Last updated: 2019-03-14Bibliographically approved
Horvath, I., Sellstedt, M., Weise, C., Nordvall, L.-M., Golla, K. P., Olofsson, A., . . . Wittung-Stafshede, P. (2013). Modulation of α-synuclein fibrillization by ring-fused 2-pyridones: templation and inhibition involve oligomers with different structure. Archives of Biochemistry and Biophysics, 532(2), 84-90
Open this publication in new window or tab >>Modulation of α-synuclein fibrillization by ring-fused 2-pyridones: templation and inhibition involve oligomers with different structure
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2013 (English)In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 532, no 2, p. 84-90Article in journal (Refereed) Published
Abstract [en]

In a recent study we discovered that a ring-fused 2-pyridone compound triggered fibrillization of a key protein in Parkinson's disease, α-synuclein. To reveal how variations in compound structure affect protein aggregation, we now prepared a number of strategic analogs and tested their effects on α-synuclein amyloid fiber formation in vitro. We find that, in contrast to the earlier templating effect, some analogs inhibit α-synuclein fibrillization. For both templating and inhibiting compounds, the key species formed in the reactions are α-synuclein oligomers that contain compound. Despite similar macroscopic appearance, the templating and inhibiting oligomers are distinctly different in secondary structure content. When the inhibitory oligomers are added in seed amounts, they inhibit fresh α-synuclein aggregation reactions. Our study demonstrates that small chemical changes to the same central fragment can result in opposite effects on protein aggregation.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
α-synuclein, amyloid, oligomer, protein aggregation, spectroscopy, 2-pyridone
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-66116 (URN)10.1016/j.abb.2013.01.012 (DOI)000317257700004 ()23399432 (PubMedID)
Available from: 2013-02-14 Created: 2013-02-14 Last updated: 2018-06-08Bibliographically approved
Horvath, I., Weise, C. F., Andersson, E. K., Chorell, E., Sellstedt, M., Bengtsson, C., . . . Wittung-Stafshede, P. (2012). Mechanisms of Protein Oligomerization: Inhibitor of Functional Amyloids Templates α-Synuclein Fibrillation. Journal of the American Chemical Society, 134(7), 3439-3444
Open this publication in new window or tab >>Mechanisms of Protein Oligomerization: Inhibitor of Functional Amyloids Templates α-Synuclein Fibrillation
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2012 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, no 7, p. 3439-3444Article in journal (Refereed) Published
Abstract [en]

Small organic molecules that inhibit functional bacterial amyloid fibers, curli, are promising new antibiotics. Here we investigated the mechanism by which the ring-fused 2-pyridone FN075 inhibits fibrillation of the curli protein CsgA. Using a variety of biophysical techniques, we found that FN075 promotes CsgA to form off-pathway, non-amyloidogenic oligomeric species. In light of the generic properties of amyloids, we tested whether FN075 would also affect the fibrillation reaction of human α-synuclein, an amyloid-forming protein involved in Parkinson's disease. Surprisingly, FN075 stimulates α-synuclein amyloid fiber formation as measured by thioflavin T emission, electron microscopy (EM), and atomic force microscopy (AFM). NMR data on (15)N-labeled α-synuclein show that upon FN075 addition, α-synuclein oligomers with 7 nm radius form in which the C-terminal 40 residues remain disordered and solvent exposed. The polypeptides in these oligomers contain β-like secondary structure, and the oligomers are detectable by AFM, EM, and size-exclusion chromatography (SEC). Taken together, FN075 triggers oligomer formation of both proteins: in the case of CsgA, the oligomers do not proceed to fibers, whereas for α-synuclein, the oligomers are poised to rapidly form fibers. We conclude that there is a fine balance between small-molecule inhibition and templation that depends on protein chemistry.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2012
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-52526 (URN)10.1021/ja209829m (DOI)22260746 (PubMedID)
Available from: 2012-02-24 Created: 2012-02-24 Last updated: 2018-06-08Bibliographically approved
Wang, C., Iashchishyn, I., Nyström, S., Klementieva, O., Kara, J., Bengtsson, S., . . . Morozova-Roche, L.S100A9-driven amyloid-neuroinflammatory cascade in traumatic brain injury as a risk factor for Alzheimer’s disease.
Open this publication in new window or tab >>S100A9-driven amyloid-neuroinflammatory cascade in traumatic brain injury as a risk factor for Alzheimer’s disease
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(English)Manuscript (preprint) (Other academic)
Keywords
Traumatic brain injury, Alzheimer’s disease, Aβ, S100A9, Amyloid, Cytotoxicity; Neuroinflammation
National Category
Other Medical Sciences not elsewhere specified
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-125077 (URN)
External cooperation:
Projects
Role of pro-inflammatory S100A9 protein in amyloid-neuroinflammatory cascade in Alzheimer’s disease and traumatic brain injury
Available from: 2016-09-05 Created: 2016-09-05 Last updated: 2018-06-07
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