dc.contributor.author |
Ng, Jin |
en |
dc.contributor.author |
Kaur, Harveen |
en |
dc.contributor.author |
Collier, Thomas |
en |
dc.contributor.author |
Chang, Kevin |
en |
dc.contributor.author |
Brooks, Anna |
en |
dc.contributor.author |
Allison, Jane |
en |
dc.contributor.author |
Brimble, Margaret |
en |
dc.contributor.author |
Hickey, Anthony |
en |
dc.contributor.author |
Birch, Nigel P |
en |
dc.date.accessioned |
2020-02-11T22:48:08Z |
en |
dc.date.issued |
2019-05 |
en |
dc.identifier.citation |
Journal of biological chemistry 294(22):8806-8818 May 2019 |
en |
dc.identifier.issn |
0021-9258 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/49915 |
en |
dc.description.abstract |
Aβ1-42 is involved in Alzheimer's disease (AD) pathogenesis and is prone to glycation, an irreversible process where proteins accumulate advanced glycated end products (AGEs). N ϵ-(Carboxyethyl)lysine (CEL) is a common AGE associated with AD patients and occurs at either Lys-16 or Lys-28 of Aβ1-42. Methyglyoxal is commonly used for the unspecific glycation of Aβ1-42, which results in a complex mixture of AGE-modified peptides and makes interpretation of a causative AGE at a specific amino acid residue difficult. We address this issue by chemically synthesizing defined CEL modifications on Aβ1-42 at Lys-16 (Aβ-CEL16), Lys-28 (Aβ-CEL28), and Lys-16 and -28 (Aβ-CEL16&28). We demonstrated that double-CEL glycations at Lys-16 and Lys-28 of Aβ1-42 had the most profound impact on the ability to form amyloid fibrils. In silico predictions indicated that Aβ-CEL16&28 had a substantial decrease in free energy change, which contributes to fibril destabilization, and a increased aggregation rate. Single-CEL glycations at Lys-28 of Aβ1-42 had the least impact on fibril formation, whereas CEL glycations at Lys-16 of Aβ1-42 delayed fibril formation. We also tested these peptides for neuronal toxicity and mitochondrial function on a retinoic acid-differentiated SH-SY5Y human neuroblastoma cell line (RA-differentiated SH-SY5Y). Only Aβ-CEL16 and Aβ-CEL28 were neurotoxic, possibly through a nonmitochondrial pathway, whereas Aβ-CEL16&28 showed no neurotoxicity. Interestingly, Aβ-CEL16&28 had depolarized the mitochondrial membrane potential, whereas Aβ-CEL16 had increased mitochondrial respiration at complex II. These results may indicate mitophagy or an alternate route of metabolism, respectively. Therefore, our results provides insight into potential therapeutic approaches against neurotoxic CEL-glycated Aβ1-42. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
The Journal of biological chemistry |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights |
This research was originally published in the Journal of Biological Chemistry. Jin Ng, Harveen Kaur, Thomas Collier, Kevin Chang, Anna E. S. Brooks, Jane R. Allison, Margaret A. Brimble, Anthony Hickey, and Nigel P. Birch Site-specific glycation of Aβ1-42 affects fibril formation and is neurotoxic. J. Biol. Chem. 2019; 294:8806-8818. © the Author(s). |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Cell Line, Tumor |
en |
dc.subject |
Mitochondria |
en |
dc.subject |
Humans |
en |
dc.subject |
Alzheimer Disease |
en |
dc.subject |
Singlet Oxygen |
en |
dc.subject |
Amyloid |
en |
dc.subject |
Lysine |
en |
dc.subject |
Peptide Fragments |
en |
dc.subject |
Apoptosis |
en |
dc.subject |
Glycosylation |
en |
dc.subject |
Membrane Potential, Mitochondrial |
en |
dc.subject |
Protein Stability |
en |
dc.subject |
Amyloid beta-Peptides |
en |
dc.subject |
Protein Aggregates |
en |
dc.subject |
Protein Conformation, beta-Strand |
en |
dc.title |
Site-specific glycation of Aβ1-42 affects fibril formation and is neurotoxic. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1074/jbc.ra118.006846 |
en |
pubs.issue |
22 |
en |
pubs.begin-page |
8806 |
en |
pubs.volume |
294 |
en |
dc.rights.holder |
Copyright: The authors |
en |
pubs.end-page |
8818 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
en |
pubs.subtype |
research-article |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
769960 |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Biological Sciences |
en |
pubs.org-id |
Chemistry |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1083-351X |
en |
pubs.record-created-at-source-date |
2019-04-19 |
en |
pubs.dimensions-id |
30996005 |
en |