liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
A protective role of lysozyme in Alzheimer disease
Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Alzheimer disease (AD) is a devastating neurodegenerative disorder where extracellular plaques composed of amyloid β (Aβ) peptides and neuroinflammation are some of the main hallmarks of the disease. Activated microglial cells, which are the resident macrophages in the central nervous system, are suggested to trigger the inflammation response in AD. To discover neuroinflammation biomarkers would be important to reveal the pathological mechanisms of AD and develop therapies that target inflammation mediators. Lysozyme is part of the innate immune system and is secreted from macrophages during various inflammation conditions. However, the involvement of lysozyme in AD pathology has not been explored previously. We have discovered that lysozyme is up-regulated in cerebrospinal fluid from AD patients. Cells exposed to Aβ increased the expression of lysozyme indicating that Aβ might be responsible for the upregulation of lysozyme detected in cerebrospinal fluid. In vitro studies revealed that lysozyme binds to monomeric Aβ1-42 and alters the aggregation pathway counteracting formation of toxic Aβ species. In a newly developed Drosophila model, co-expression of lysozyme with Aβ in brain neurons reduced the formation of insoluble Aβ species, prolonged the survival and improved the activity of the double transgenic flies compared to flies only expressing Aβ. Our findings identify lysozyme as a modulator of Aβ aggregation and toxicity and our discoveries has the potential to be used for development of new treatment strategies and to use lysozyme as a biomarker for AD.

Keyword [en]
Lysozyme, Biomarker, Alzheimer disease, Drosophila, CSF, Aβ aggregation
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-106646OAI: oai:DiVA.org:liu-106646DiVA: diva2:717661
Available from: 2014-05-16 Created: 2014-05-16 Last updated: 2014-05-16Bibliographically approved
In thesis
1. Understanding the dual nature of lysozyme: part villain – part hero: A Drosophila melanogaster model of lysozyme amyloidosis
Open this publication in new window or tab >>Understanding the dual nature of lysozyme: part villain – part hero: A Drosophila melanogaster model of lysozyme amyloidosis
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyloid proteins are a distinct class of proteins that can misfold into β-sheet rich structures that later mature to form the characteristic species known as amyloid fibrils, and accumulate in tissues in the human body. The misfolding event is often caused by mutations (or outer factors such as changes in pH) that destabilize the native protein structure. The mature amyloid fibrils were initially believed to be associated with diseases connected to protein misfolding such as Alzheimer’s disease (AD), Parkinson’s disease, transthyretin amyloidosis and lysozyme amyloidosis. However, now it is known that many different factors are involved in these diseases such as failure in protein clearance, lysosomal dysfunction and formation of intermediate misfolded protein species, which possess cytotoxic properties, preceding the formation of mature fibrils.

In this thesis the amyloidogenic protein lysozyme has been examined in vivo by using Drosophila melanogaster (fruit fly) as a model organism. The effects of over-expressing human lysozyme and amyloidogenic variants in Drosophila have been investigated both in the absence and presence of the serum amyloid P component (SAP), a protein known to interact with amyloid species. In addition, the role of lysozyme in AD has been investigated by  co-expressing human lysozyme and amyloid β in Drosophila.

The lysozyme protein is an enzyme naturally found in bodily fluids such as tears, breast milk and saliva. It is engaged in the body’s defense and acts by hydrolyzing the cell wall of invading bacteria. Certain disease-associated point mutations in the gene encoding lysozyme destabilize the protein and cause it to misfold which results in systemic amyloidosis. To investigate the in vivo misfolding behavior of lysozyme we developed and established a Drosophila model of lysozyme amyloidosis. SAP is commonly found attached to amyloid deposits in the body; however, the role of SAP in amyloid diseases is unknown. To investigate the effect of SAP in lysozyme misfolding, these two proteins were co-expressed in Drosophila.

The amyloid β peptide is involved in AD, building up the plaques found in AD patient brains. These plaques trigger neuroinflammation and since lysozyme is upregulated during various inflammation conditions, a possible role of lysozyme in AD was investigated by overexpressing lysozyme in a Drosophila model of AD. Interaction between lysozyme and the amyloid β protein was also studied by biophysical measurements.

During my work with this thesis, the dual nature of lysozyme emerged; on the one hand a villain, twisted by mutations, causing the lysozyme amyloidosis disease. On the other hand a hero, delaying the toxicity and maybe the neurological damage caused by the amyloid β peptide.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 67 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1574
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-106647 (URN)10.3384/diss.diva-106647 (DOI)978-91-7519-405-9 (ISBN)
Public defence
2014-05-05, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 10:15 (English)
Opponent
Supervisors
Available from: 2014-05-16 Created: 2014-05-16 Last updated: 2014-05-19Bibliographically approved

Open Access in DiVA

No full text

Authority records BETA

Helmfors, LindaArmstrong, AndreaCivitelli, LiviaSandin, LinneaNath, SangeetaJanefjord, CamillaBrorsson, Ann-ChristinKågedal, Katarina

Search in DiVA

By author/editor
Helmfors, LindaArmstrong, AndreaCivitelli, LiviaSandin, LinneaNath, SangeetaJanefjord, CamillaBrorsson, Ann-ChristinKågedal, Katarina
By organisation
Department of Physics, Chemistry and BiologyThe Institute of TechnologyDivision of Cell BiologyFaculty of Health SciencesDepartment of Clinical and Experimental MedicineChemistry
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 309 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf