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The Alzheimer Aβ Peptide: Identification of Properties Distinctive for Toxic Prefibrillar Species
Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
2012 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins must have specific conformations to function correctly inside cells. However, sometimes they adopt the wrong conformation, causing dysfunction and disease. A number of amyloid diseases are caused by misfolded proteins that form amyloid fibrils. One such disease is Alzheimer’s disease (AD). The protein involved in this deadly disease is the amyloid β (Aβ) peptide. The formation of soluble prefibrillar oligomeric Aβ species has been recognized as an important factor in the development of AD. The aim of work described in this thesis was to investigate which properties of these oligomeric species can be linked to toxicity. We approached this task by comparing the aggregation behavior and biophysical properties of aggregates formed by variants of the Aβ peptide that have been shown to differ in neurotoxicity when expressed in the central nervous system (CNS) of Drosophila melanogaster. A combined set involving different fluorescent probes was used in parallell with transmission electron microscopy. The toxicity of species formed during the aggregation process was examined by exposing human SH-SY5Y neuroblastoma cells to Aβ aggregates. We deduced that there is a correlation between cell toxicity and the propensity of the Aβ peptide to form small prefibrillar assemblies at an early stage of aggregation in vitro. Moreover, these prefibrillar species were characterized by their ability to be recognized by pentamer formyl thiophene acetic acid (p-FTAA) and the presence of exposed hydrophobic patches. We also found that larger aggregates did not induce cell death.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. , 44 p.
Series
Linköping Studies in Science and Technology. Thesis, ISSN 0280-7971 ; 1526
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-76741Local ID: LIU-TEK-LIC-2012:11ISBN: 978-91-7519-930-6 (print)OAI: oai:DiVA.org:liu-76741DiVA: diva2:516577
Presentation
2012-04-20, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 10:15 (English)
Opponent
Available from: 2012-04-18 Created: 2012-04-18 Last updated: 2012-12-04Bibliographically approved
List of papers
1. Identification of distinct physiochemical properties of the toxic prefibrillar species formed by Aβ peptide variants
Open this publication in new window or tab >>Identification of distinct physiochemical properties of the toxic prefibrillar species formed by Aβ peptide variants
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2012 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 420, no 4, 895-900 p.Article in journal (Refereed) Published
Abstract [en]

The formation of amyloid-β peptide (Aβ) aggregates at an early stage during the self-assembly process is an important factor in the development of Alzheimer’s disease. The toxic effect is believed to be exerted by prefibrillar species of Aβ. It is therefore important to identify which prefibrillar species are toxic and characterize their distinct properties. In the present study, we investigated the in vitro aggregation behavior of Aβ-derived peptides possessing different levels of neurotoxic activity, using fluorescence spectroscopy in combination with transmission electron microscopy. The toxicity of various Aβ aggregates was assessed by using cultures of human neuroblastoma cells. Through combined use of the fluorescence probe 8-anilino-1-napthalenesulfonate (ANS) and the novel luminescent probe pentamer formyl thiophene acetic acid (p-FTAA), we were able to identify those Aβ peptide-derived prefibrillar species which exhibited cellular toxicity. In particular, species, which formed early during the aggregation process and showed strong p-FTAA and ANS fluorescence, were the species that possessed toxic activities. Moreover, by manipulating the aggregation conditions, it was possible to change the capacity of the Aβ peptide to form nontoxic versus toxic species.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-73185 (URN)10.1016/j.bbrc.2012.03.097 (DOI)000303619100034 ()
Note

funding agencies|Swedish National Graduate School in Science, Technology and Mathematics Education Research (Fon-tD)||Swedish Alzheimers Foundation||Soderberg foundation||

Available from: 2011-12-21 Created: 2011-12-21 Last updated: 2017-12-08Bibliographically approved
2. Dissecting the Aggregation Events of Alzheimer’s disease Associated Aβ peptide Variants by the Combined use of Different Fluorescent Probes
Open this publication in new window or tab >>Dissecting the Aggregation Events of Alzheimer’s disease Associated Aβ peptide Variants by the Combined use of Different Fluorescent Probes
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The formation of soluble prefibrillar oligomeric species of the amyloid β peptide (Aβ) has been implicated as a causative agent in the development of Alzheimer’s disease (AD). It is therefore important to characterize the properties of these aggregates, which precede the formation of amyloid fibrils. We studied the in vitro aggregation process of two Aβ40 peptide variants through the combined use of four different fluorescent probes and transmission electron microscopy. Previous studies have shown that these two studied Aβ40 variants exhibit different levels of neurodegeneration when expressed in the central nervous system of Drosophila melanogaster. In the present study, we demonstrate distinct differences in aggregate morphology and their binding properties to different fluorescent probes during in vitro fibrillation of these Aβ peptides. Our results indicate a potential link between the observed neurodegenerative properties and the biophysical properties of distinct aggregated Aβ species.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-76739 (URN)
Available from: 2012-04-18 Created: 2012-04-18 Last updated: 2014-04-08

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Göransson, Anna-Lena

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