Brinkmalm, G;
Hong, W;
Wang, Z;
Liu, W;
O'Malley, TT;
Sun, X;
Frosch, MP;
... Walsh, DM; + view all
(2019)
Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain.
Brain
, 142
(5)
pp. 1441-1457.
10.1093/brain/awz066.
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Abstract
The primary structure of canonical amyloid-β-protein was elucidated more than 30 years ago, yet the forms of amyloid-β that play a role in Alzheimer’s disease pathogenesis remain poorly defined. Studies of Alzheimer’s disease brain extracts suggest that amyloid-β, which migrates on sodium dodecyl sulphate polyacrylamide gel electrophoresis with a molecular weight of ∼7 kDa (7kDa-Aβ), is particularly toxic; however, the nature of this species has been controversial. Using sophisticated mass spectrometry and sensitive assays of disease-relevant toxicity we show that brain-derived bioactive 7kDa-Aβ contains a heterogeneous mixture of covalently cross-linked dimers in the absence of any other detectable proteins. The identification of amyloid-β dimers may open a new phase of Alzheimer’s research and allow a better understanding of Alzheimer’s disease, and how to monitor and treat this devastating disorder. Future studies investigating the bioactivity of individual dimers cross-linked at known sites will be critical to this effort.
| Type: | Article |
|---|---|
| Title: | Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/brain/awz066 |
| Publisher version: | https://doi.org/10.1093/brain/awz066 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Amyloid β-protein, long-term potentiation, human neurons, mass spectrometry, videomicroscopy. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10073499 |
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