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Heparan Sulfate Dependent Mechanisms of Amyloidosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Jin-Ping Li)
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A common theme in amyloid disorders is the deposition of disease-specific protein aggregates in tissues. Amyloid proteins bind to heparan sulfate (HS), a sulfated glycosaminoglycan, and HS has been found to promote the aggregation process. The present work relates to HS mediated mechanisms of amyloidosis, particularly transthyretin (TTR) amyloidosis, AA-amyloidosis and Alzheimer’s disease (AD).

TTR is a transport protein present in the blood and cerebrospinal fluid, which under unclear circumstances can deposit as amyloid in the myocardium of elderly individuals. Examination of cardiac tissue from a 70 year old patient with reported cardiomyopathy reveald co-deposition of TTR amyloid and HS. Studies revealed that HS promotes TTR fibrillization through interaction with a basic motif in the protein. Empolyment of a cell model demonstrated that cell surface HS mediates internalization of TTR, an effect likely facilitated by HS-binding to the basic motif on TTR. Collectively, HS-TTR interactions at the cell surface may have dual outcomes, resulting in either fibrillization or internalization, respectively.

During inflammatory conditions, serum amyloid A (SAA), an acute-phase protein associated with the high-density lipoprotein (HDL), can assemble into insoluble amyloid fibrils, causing AA-amyloidosis. We found that HS structures exceeding 12-14 sugar units in length separates SAA from HDL and induces subsequent aggregation of the polypeptide. Our result proposes a novel role for HS in AA-amyloidosis in which a critical length of HS is required for separation of SAA from HDL.

Late-onset AD patients show reduced ability to clear cerebral amyloid-β (Aβ) aggregates, a pathological hallmark of the disease. Althought the pathway of Aβ clearance is still unclear, several cell-surface receptors are implicated in Aβ internalization. We found that ApoE facilitated Aβ uptake through interactions with HS-proteoglycans and low-density lipoprotein receptor-related protein 1. The ApoE interaction with Aβ likely promotes Aβ clearance in the brain, but, if unbalanced, may contribute to the pathology of AD.    

These findings are in accord with the concept of HS as a promoter of amyloid protein aggregation, but also point to more complex relationship.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2012. , 41 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 740
Keyword [en]
Amyloidosis, Heparan sulfate, Transthyretin, Serum amyloid A, Amyloid-beta, lipoproteins
National Category
Biochemistry and Molecular Biology
Research subject
Medical Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-168309ISBN: 978-91-554-8272-5 (print)OAI: oai:DiVA.org:uu-168309DiVA: diva2:492898
Public defence
2012-03-23, B42, BMC, Husargatan 3, Uppsala, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-03-01 Created: 2012-02-08 Last updated: 2012-03-29Bibliographically approved
List of papers
1.
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2. Heparan sulfate mediates transthyretin internalization
Open this publication in new window or tab >>Heparan sulfate mediates transthyretin internalization
(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-168313 (URN)
Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2012-03-29
3. Heparan sulfate/heparin-HDL interaction dissociates serum amyloid A (SAA) from HDL-SAA complex leading to SAA aggregation
Open this publication in new window or tab >>Heparan sulfate/heparin-HDL interaction dissociates serum amyloid A (SAA) from HDL-SAA complex leading to SAA aggregation
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2012 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 30, 25669-25677 p.Article in journal (Refereed) Published
Abstract [en]

Inflammation-related (AA) amyloidosis is a severe clinical disorder characterized by the systemic deposition of the acute-phase reactant serum amyloid A (SAA). SAA is normally associated with the high-density lipoprotein (HDL) fraction in plasma, but under yet unclear circumstances, the apolipoprotein is converted into amyloid fibrils. AA amyloid and heparan sulfate (HS) display an intimate relationship in situ, suggesting a role for HS in the pathogenic process. This study reports that HS dissociates SAA from HDLs isolated from inflamed mouse plasma. Application of surface plasmon resonance spectroscopy and molecular modeling suggests that HS simultaneously binds to two apolipoproteins of HDL, SAA and ApoA-I, and thereby induce SAA dissociation. The activity requires a minimum chain length of 12-14 sugar units, proposing an explanation to previous findings that short HS fragments preclude AA amyloidosis. The results address the initial events in the pathogenesis of AA amyloidosis.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-168314 (URN)10.1074/jbc.M112.363895 (DOI)000306651700074 ()
Note

Manuscript title: Heparan sulfate/heparin-HDL interaction dissociates serum amyloid A (SAA) from HDL-SAA complex leading to SAA aggregation

Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2017-12-08Bibliographically approved
4. Apolipoprotein E increases cell association of amyloid-β 40 through heparan sulfate and LRP1 dependent pathways
Open this publication in new window or tab >>Apolipoprotein E increases cell association of amyloid-β 40 through heparan sulfate and LRP1 dependent pathways
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2014 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 21, no 2, 76-87 p.Article in journal (Refereed) Published
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-168315 (URN)10.3109/13506129.2013.879643 (DOI)000336146700002 ()
Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2017-12-08

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