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Amyloid formation by the pro-inflammatory S100A8/A9 proteins in the ageing prostate
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
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2009 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 5, e5562- p.Article in journal (Refereed) Published
Abstract [en]

Background The conversion of soluble peptides and proteins into polymeric amyloid structures is a hallmark of many age-related degenerative disorders, including Alzheimer's disease, type II diabetes and a variety of systemic amyloidoses. We report here that amyloid formation is linked to another major age-related phenomenon - prostate tissue remodelling in middle-aged and elderly men.

Methodology/Principal Findings By using multidisciplinary analysis of corpora amylacea inclusions in prostate glands of patients diagnosed with prostate cancer we have revealed that their major components are the amyloid forms of S100A8 and S100A9 proteins associated with numerous inflammatory conditions and types of cancer. In prostate protease rich environment the amyloids are stabilized by dystrophic calcification and lateral thickening. We have demonstrated that material closely resembling CA can be produced from S100A8/A9 in vitro under native and acidic conditions and shows the characters of amyloids. This process is facilitated by calcium or zinc, both of which are abundant in ex vivo inclusions. These observations were supported by computational analysis of the S100A8/A9 calcium-dependent aggregation propensity profiles. We found DNA and proteins from Escherichia coli in CA bodies, suggesting that their formation is likely to be associated with bacterial infection. CA inclusions were also accompanied by the activation of macrophages and by an increase in the concentration of S100A8/A9 in the surrounding tissues, indicating inflammatory reactions.

Conclusions/Significance These findings, taken together, suggest a link between bacterial infection, inflammation and amyloid deposition of pro-inflammatory proteins S100A8/A9 in the prostate gland, such that a self-perpetuating cycle can be triggered and may increase the risk of malignancy in the ageing prostate. The results provide strong support for the prediction that the generic ability of polypeptide chains to convert into amyloids could lead to their involvement in an increasing number of otherwise apparently unrelated diseases, particularly those associated with ageing.

Place, publisher, year, edition, pages
2009. Vol. 4, no 5, e5562- p.
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
URN: urn:nbn:se:umu:diva-22971DOI: 10.1371/journal.pone.0005562OAI: oai:DiVA.org:umu-22971DiVA: diva2:218819
Available from: 2009-05-25 Created: 2009-05-25 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Studies of in vivo prostate amyloidosis and autoimmune responses towards amyloid structures in neurodegeneration
Open this publication in new window or tab >>Studies of in vivo prostate amyloidosis and autoimmune responses towards amyloid structures in neurodegeneration
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Studier av in vivo prostata amyloidos och autoimmunitet mot amyloida strukturer vid neurodegenerativa sjukdomar
Abstract [en]

By using multidisciplinary analysis of CA inclusions in prostate glands of patients diagnosed with prostate cancer, we have revealed that their major components are the amyloid forms of S100A8 and S100A9 proteins associated with numerous inflammatory conditions and types of cancer. We have demonstrated that material closely resembling CA can be produced from S100A8/A9 in vitro and shows the characters of amyloids. This process is facilitated by calcium or zinc, both of which are abundant in ex vivo inclusions. These observations were supported by computational analysis of the S100A8/A9 calcium-dependent aggregation propensity profiles. We have found DNA and proteins from Escherichia coli in CA bodies, suggesting that their formation is likely to be associated with bacterial infection. CA inclusions were also accompanied by the activation of macrophages and by an increase in the concentration of S100A8/A9 in the surrounding tissues, indicating inflammatory reactions. These findings, taken together, suggest a link between bacterial infection, inflammation and amyloid deposition of pro-inflammatory proteins S100A8/A9 in the prostate gland, such that a self-perpetuating cycle can be triggered and may increase the risk of malignancy in the ageing prostate.

We evaluated the autoimmune reactions to endocrine (insulin) and astrocytical (S100B) biomarkers in the blood sera of PD patients compared with healthy controls. Peripheral immune responses can be sensitive indicators of disease pathology. We found a statistically significant increase of the autoimmune responses to both antigens in patients compared with controls. Heterogeneity of the immune responses observed in patients may reflect the modulating effect of multiple variables associated with neurodegeneration and also changes in the basic mechanisms of individual autoimmune reactivity. We did not detect any pronounced immune reactions towards insulin amyloid fibrils and oligomers in patients, indicating that an amyloid-specific conformational epitope is not involved in immune recognition of this amyloid type. Immune reactions towards S100B and insulin may reflect the neurodegenerative brain damaging processes and impaired insulin homeostasis occurring in PD.

Generated auto-antibodies towards the major amyloidogenic protein involved in PD Lewy bodies - a-synuclein and its amyloid oligomers and fibrils were measured in the blood sera of early and late PD patients and controls by using ELISA, Western blot and Biacore surface plasmon resonance analyses. We found significantly higher antibody levels towards monomeric a-synuclein in the blood sera of PD patients compared to controls, though the responses decreased with PD progression. There were no noticeable immune responses towards amyloid oligomers, but substantially increased levels of IgGs towards a-synuclein amyloid fibrils both in PD patients and controls, which subsided with the disease progression. Pooled IgGs from PD patients and controls interacted also with amyloid fibrils of Ab (1-40) and hen lysozyme, however the latter were recognized with lower affinity. This suggests that IgGs bind to amyloid conformational epitope, though displaying higher specificity towards human amyloid species associated with neurodegeneration. The findings suggest the protective role of autoimmunity in PD and therefore immune reactions towards PD major amyloid protein - a-synuclein can be used in treatment strategies and in diagnostics, especially in identifying early disease.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2010. 40 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1386
Keyword
amyloid, amyloidosis, immune reactivity, S100A8/A9, insulin, α-synuclein
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-37561 (URN)978-91-7459-110-1 (ISBN)
Public defence
2010-12-01, KB3A9, Umeå University, Umeå, KBC building, 09:00 (English)
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Available from: 2010-11-12 Created: 2010-11-09 Last updated: 2012-08-15Bibliographically approved

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Yanamandra, KiranAlexeyev, OlegZamotin, VladimirSrivastava, VaibhavShchukarev, AndreyWingsle, GunnarOlsson, JanBergh, AndersElgh, FredrikMorozova-Roche, Ludmilla A
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Department of Medical Biochemistry and BiophysicsPathologyUmeå Plant Science Centre (UPSC)Department of ChemistryVirology
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