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Amyloid aggregates: detection and interaction

Rahman, Mahafuzur (2018). Amyloid aggregates: detection and interaction. Diss. (sammanfattning/summary) Uppsala, Sweden : Sveriges lantbruksuniv., Acta Universitatis agriculturae Sueciae, 1652-6880 ; 2018:58
ISBN 978-91-7760-256-9
eISBN 978-91-7760-257-6
[Doctoral thesis]

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Abstract

The research on protein aggregation and amyloid formation is motivated by the fact that amyloid formation in tissue is harmful and associated with several debilitating diseases including Alzheimer’s disease (AD) and systemic amyloidosis such as transthyretin (ATTR) amyloidosis. Nevertheless, their beneficial roles in Nature have recently been identified, and artificial self-assembling of amyloid structure for various applications are emerging. In this thesis, disease-related amyloid aggregates were studied with a focus on their detection and interactions with other proteins in biofluid. Also, the usefulness of functionalized self-assembled amyloid structure as a detection system for pathological amyloid is investigated.

New affinity proteins based on Affibody molecules were developed targeting stable protofibrils formed by an engineered version of amyloid-β (Aβ) peptide, called Aβ42CC. The developed affinity proteins also recognize protofibrils of wild-type Aβ42, and showed selective binding to protofibrils over other aggregated forms of Aβ. Binding kinetics of these new binders to Aβ42CC protofibrils were determined. These proteins have potential to be used in diagnostic or even therapeutic applications.

An enhanced method was developed for the detection of small ATTR aggregates. A nanofibril, which was functionalized with the antibody-binding Z domain was the new molecule in the improved method. The efficiency of the new method for sensitive detection of ATTR aggregates was studied. The result of this study was very encouraging and could potentially be used in the future for high sensitivity detection of ATTR aggregates.

The potential interactions of Aβ42CC protofibrils and Aβ42wt fibrils with other proteins in serum and cerebrospinal fluid from patients with AD and non-AD were studied. More than hundred proteins with diverse functionality were identified to bind to Aβ42CC protofibrils and Aβ42wt fibrils. It was shown that different Aβ conformations have a distinct set of binding partners, and the binding is enhanced upon aggregation of Aβ. Many of the identified proteins may have potential as AD biomarkers.

In conclusion, this thesis has developed new research tools and a methodology to detect amyloid aggregates as well as studied potential interactions of these aggregates with other proteins, which could advance our understanding about protein aggregation and disease.

Authors/Creators:Rahman, Mahafuzur
Title:Amyloid aggregates: detection and interaction
Series/Journal:Acta Universitatis agriculturae Sueciae (1652-6880)
Year of publishing :7 November 2018
Depositing date:7 November 2018
Volume:2018:58
Number of Pages:73
Papers/manuscripts:
NumberReferences
I.Wahlberg E *, Rahman MM*, Lindberg H, Gunneriusson E, Schmuck B, Lendel, Sandgren M, Löfblom J, Ståhl S, Härd T (2017). Identification of proteins that specifically recognize and bind protofibrillar aggregates of amyloid-β. Sci Rep, vol. 7 (1), pp. 5949.
II.Rahman MM, Schmuck B, Hansson H, Westermark GT, Härd T, Sandgren M (2018). Enhanced detection of pathological ATTR aggregates using a nanofibril-based assay. (Manuscript)
III.Rahman MM, Zetterberg H, Lendel C, Härd T (2015). Binding of human proteins to amyloid‐β protofibrils. ACS Chem Biol, vol.10 (3), pp. 766–774.
IV.Rahman MM, Westermark GT, Zetterberg H, Härd T, Sandgren M (2018). Protofibrillar and fibrillar amyloid β-binding proteins in cerebrospinal fluid. JAD, DOI 10.3233/JAD-180596, E-pub ahead of print.
Place of Publication:Uppsala, Sweden
Publisher:Department of Molecular Sciences, Swedish University of Agricultural Sciences
ISBN for printed version:978-91-7760-256-9
ISBN for electronic version:978-91-7760-257-6
ISSN:1652-6880
Language:English
Publication Type:Doctoral thesis
Full Text Status:Public
Agris subject categories.:X Agricola extesions > X30 Life sciences
Subjects:(A) Swedish standard research categories 2011 > 1 Natural sciences > 106 Biological Sciences (Medical to be 3 and Agricultural to be 4) > Biochemistry and Molecular Biology
Keywords:Alzheimer’s disease, amyloid, detection, functional amyloid, interaction, protein aggregation, transthyretin
URN:NBN:urn:nbn:se:slu:epsilon-e-5099
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-e-5099
ID Code:15738
Faculty:NJ - Fakulteten för naturresurser och jordbruksvetenskap
Department:(NL, NJ) > Department of Molecular Sciences
Deposited By: Mahafuzur Rahman
Deposited On:08 Nov 2018 09:31
Metadata Last Modified:15 Nov 2018 19:21

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