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Studies of in vivo prostate amyloidosis and autoimmune responses towards amyloid structures in neurodegeneration
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. (Ludmilla Morozova-Roche group)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Studier av in vivo prostata amyloidos och autoimmunitet mot amyloida strukturer vid neurodegenerativa sjukdomar (Swedish)
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 [en]
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: urn:nbn:se:umu:diva-37561ISBN: 978-91-7459-110-1 (print)OAI: oai:DiVA.org:umu-37561DiVA: diva2:362981
Public defence
2010-12-01, KB3A9, Umeå University, Umeå, KBC building, 09:00 (English)
Opponent
Supervisors
Available from: 2010-11-12 Created: 2010-11-09 Last updated: 2012-08-15Bibliographically approved
List of papers
1. Amyloid formation by the pro-inflammatory S100A8/A9 proteins in the ageing prostate
Open this publication in new window or tab >>Amyloid formation by the pro-inflammatory S100A8/A9 proteins in the ageing prostate
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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.

National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-22971 (URN)10.1371/journal.pone.0005562 (DOI)
Available from: 2009-05-25 Created: 2009-05-25 Last updated: 2017-12-13Bibliographically approved
2. Immune reactivity towards insulin, its amyloid and protein S100B in blood sera of Parkinson's disease patients
Open this publication in new window or tab >>Immune reactivity towards insulin, its amyloid and protein S100B in blood sera of Parkinson's disease patients
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2007 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 14, no 3, 327-334 p.Article in journal (Refereed) Published
Abstract [en]

Peripheral immune responses can be sensitive indicators of disease pathology. We evaluated the autoimmune reactions to endocrine (insulin) and astrocytical (S100B) biomarkers in the blood sera of 26 Parkinson's disease (PD) patients compared with controls by using ELISA. We found a statistically significant increase of the autoimmune responses to both antigens in PD patients compared with controls with a mean increase of 70% and 50% in the autoimmune reactions towards insulin and S100B, respectively. 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 PD patients, indicating that an amyloid-specific conformational epitope is not involved in immune recognition of this amyloid type, while sequential epitope of native insulin is hidden within the amyloid structures. Immune reactions towards S100B and insulin may reflect the neurodegenerative brain damaging processes and impaired insulin homeostasis occurring in PD.

Keyword
amyloid;immune reactivity;insulin;Parkinson's disease;S100B
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-25729 (URN)10.1111/j.1468-1331.2006.01667.x (DOI)17355556 (PubMedID)
Available from: 2009-09-01 Created: 2009-09-01 Last updated: 2017-12-13Bibliographically approved
3. Alpha-Synuclein Reactive Antibodies as Diagnostic Biomarkers in Blood Sera of Parkinson's Disease Patients
Open this publication in new window or tab >>Alpha-Synuclein Reactive Antibodies as Diagnostic Biomarkers in Blood Sera of Parkinson's Disease Patients
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2011 (English)In: PLoS One, ISSN 1932-6203, Vol. 6, no 4, e18513- p.Article in journal (Refereed) Published
Abstract [en]

Background

Auto-antibodies with specificity to self-antigens have been implicated in a wide variety of neurological diseases, including Parkinson's (PD) and Alzheimer's diseases, being sensitive indicators of neurodegeneration and focus for disease prevention. Of particular interest are the studies focused on the auto-immune responses to amyloidogenic proteins associated with diseases and their applications in therapeutic treatments such as vaccination with amyloid antigens and antibodies in PD, Alzheimer's disease and potentially other neurodegeneration ailments.

Methodology/Principal Findings

Generated auto-antibodies towards the major amyloidogenic protein involved in PD Lewy bodies – α-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. We found significantly higher antibody levels towards monomeric α-synuclein in the blood sera of PD patients compared to controls, though the responses decreased with PD progression (P<0.0001). This indicates potential protective role of autoimmunity in maintaining the body homeostasis and clearing protein species whose disbalance may lead to amyloid assembly. There were no noticeable immune responses towards amyloid oligomers, but substantially increased levels of IgGs towards α-synuclein amyloid fibrils both in PD patients and controls, which subsided with the disease progression (P<0.0001). Pooled IgGs from PD patients and controls interacted also with the amyloid fibrils of Aβ (1–40) and hen lysozyme, however the latter were recognized with lower affinity. This suggests that IgGs bind to the generic amyloid conformational epitope, displaying higher specificity towards human amyloid species associated with neurodegeneration.

Conclusions/Significance

Our findings may suggest the protective role of autoimmunity in PD and therefore immune reactions towards PD major amyloid protein – α-synuclein can be of value in the development of treatment and diagnostic strategies, especially during the early disease stages.

Place, publisher, year, edition, pages
Public Library of Science, 2011
Keyword
amyloid, biomarker, Parkinson's disease
National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
urn:nbn:se:umu:diva-43962 (URN)10.1371/journal.pone.0018513 (DOI)
Projects
amyloid research
Available from: 2011-05-16 Created: 2011-05-16 Last updated: 2012-08-15Bibliographically approved

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